Comprehensive Physiology Wiley Online Library

Molecular Events in Growth Hormone–Receptor Interaction and Signaling

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 The Growth Hormone Receptor
1.1 Cloning of the Growth Hormone Receptor
1.2 The Cytokine/Hematopoietin Receptor Superfamily
1.3 Growth Hormone Binding and Receptor Dimerization
2 Growth Hormone–Dependent Intracellular Signaling
2.1 Activation of the Tyrosine Kinase Janus Kinase 2
2.2 Tyrosyl Phosphorylation of the Growth Hormone Receptor and Janus Kinase 2
2.3 Activation of the Ras–Mitogen‐Activated Protein Kinase Signaling Pathway
2.4 Utilization of Insulin Receptor Substrates 7 and 2 and Phosphatidylinositol‐3′‐Kinase
2.5 Regulation of Protein Kinase C
2.6 Regulation of Intracellular Calcium
2.7 Activation of Stat Proteins
3 Growth Hormone‐Dependent Signaling to the Nucleus
3.1 Multiple Pathways Mediate Growth Hormone–Regulated Gene Expression
3.2 Sexually Dimorphic Growth Hormone Secretion Patterns Regulate Gene Transcription
4 Conclusions
Figure 1. Figure 1.

Members of the cytokine receptor superfamily are schematically illustrated, including the specific receptors (R) for growth hormone (GH); prolactin (PRL); erythropoietin (EPO); granulocyte colony‐stimulating factor (G‐CSF); ciliary neurotrophic factor (CNTP); leukemia‐inhibitory factor (LIF); oncostatin M (OSM); leptin (Ob‐Rb); thrombopoietin (mpl); granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); interleukins (IL) 2–7, 9–13, and 15; and interferon (IFN)‐γ and‐α as well as shared receptor subunits including the IL‐3 receptor common β chain (Aic‐2/βc), the IL‐2 receptor common γ chain (γc), and gp 130. Conserved extracellular cysteine motifs are represented by four thin lines. Extracellular WSXWS motifs are represented by black boxes (a thinner box represents WSXWS‐like motifs with conservative substitutions). Numbered white boxes in the intracellular region represent the conserved Box 1 and Box 2 regions. Dotted lines indicate putative receptor complexes employed by ligand.

From , with permission
Figure 2. Figure 2.

Growth hormone (GH) increases tyrosyl phosphorylation of multiple cellular proteins in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were treated with or without 23 nM (500 ng/ml) GH for the indicated times at 37°C. Whole‐cell lysates were prepared, fractionated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes. The resulting blot was probed with antiphosphotyrosine antibody. Eleven novel tyrosyl‐phosphorylated bands are observed in response to GH, indicating that GH induces tyrosyl phosphorylation of multiple proteins.

From , with permission
Figure 3. Figure 3.

Growth hormone (GH) induces Janus kinase (JAK2) activity and tyrosyl phosphorylation. A: Cells, 3T3–F442A, were incubated at 25°C in the absence (lane A) or presence (lanes B–D) of 30 ng/ml human GH for 1 h. Solubilized proteins were immunoprecipitated using anti‐JAK2 antibody, incubated with [γ – 32P] ATP, and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and autoradiography (lanes A and B). The presence of a dark band in lane B, but not in lane A, indicates that GH activates JAK2, as assessed by JAK2 autophosphorylation. Then, JAK2 was excised from the gel (lane B) and subjected to limited acid hydrolysis at 109°C for 1.25 h. Following partial purification on Dowex‐50, fractions containing O‐phosphoserine and O‐phosphothreonine (lane C) or O‐phosphotyrosine (lane D) were resolved by thin‐layer electrophoresis (pH 3.5). Migrations of O‐phosphoserine (P‐Ser), O‐phosphothreonine (P‐Thr), and O‐phosphotyrosine (P‐Tyr) standards are indicated by the dashed circles. Greater than 99% of the 32P incorporated into JAK2 in the in vitro kinase assay co‐migrated with O‐phosphotyrosine, indicating that JAK2 is a tyrosine kinase. B: Fibroblasts, 3T3–F442A, were incubated with the indicated concentrations of human GH for the times shown. Whole‐cell lysates were immunoprecipitated with antibody to JAK2. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. The GH‐dependent signal indicates that in intact cells JAK2 is tyrosyl‐phosphorylated in response to GH.

Part A from , with permission; part B from , with permission
Figure 4. Figure 4.

Growth hormone (GH) receptor. Potential N‐linked glycosylation sites (N) and the extracellular cysteines (C) with three pairs of linked disulfide bonds are noted. The transmembrane domain is shown in black. The ten tyrosines (Y) present in the cytoplasmic region of rat GH receptor are noted. The position of the WSXWS‐like motif is indicated by the striped box. Intracellular Box 1 (proline‐rich domain) and Box 2 are shown as gray boxes. Regions of the receptor required for various functions are indicated. MAP, mitogen‐activated protein; JAK, Janus kinase; IRS, insulin receptor substrate.

From , with permission
Figure 5. Figure 5.

Possible signaling pathways initiated by binding of growth hormone (GH) to its receptor are shown. Solid arrows indicate pathways regulated by GH. Dotted arrows indicate pathways utilized by other growth factors but not yet shown to be involved in GH‐dependent signal transduction or pathways with only limited data to support their existence. P, phosphorylated tyrosines; JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol‐3‐kinase; PC‐PLC, phosphocholine–phospholipase C; DAG, diacylglycerol; PKC, protein kinsase C; SOS, son of sevenless; MAPK, mitogen‐activated protein kinase; MEK, MAPK/ERK kinase; PLA2; phospholipase A2; SRF, serum response factor; TCF, ternary complex factor; SIE, Sis‐inducible element; SRE, serum response elements; AP1, activator protein‐1; GLE, interferon‐γ‐activated sequence–like element.

From , with permission
Figure 6. Figure 6.

Growth hormone (GH) activates extracellular signal–regulated kinases (ERKs) 1 and 2. Fibroblasts, 3T3–F442A, were incubated with 23 nM (500 ng/ml) human GH for the times indicated. Whole‐cell lysates were blotted with an antibody which detects only the active, doubly phosphorylated form of ERKs 1 and 2. The GH‐dependent signal observable by 5 min indicates that GH induces phosphorylation and activation of ERKs 1 and 2.

Figure 7. Figure 7.

Growth hormone receptor (GHR) signaling via the extracellular signal–regulated kinases (ERKs) 1 and 2. A signaling cascade leading from GHR to the mitogen‐activated protein (MAP) kinase and activation of subsequent targets is shown. Solid arrows and signaling molecules and bold targets indicate pathways and proteins regulated by GH. Dotted arrows and targets in medium type indicate pathways, feedback mechanisms, and targets utilized in cells treated with other cytokines and growth factors that activate MAP kinase or are detected in vitro. These have not yet been shown to be involved in GH signal transduction. PLC, phospholipase C; PLA2, phospholipase A2; TCF, ternary complex factor; JAK, Janus kinase; GTP, guanosine triphosphate; Sos, son of sevenless; MEK, MAP kinase/ERK kinase. TAL, T‐cell acute lymphoblastic leukemia gene; NF, nuclear factor IL‐6; ATF, activating transcription factor‐2; MAPKAP, MAP kinase activated protein kinase‐2.

Figure 8. Figure 8.

Growth hormone (GH) promotes tyrosyl phosphorylation of insulin receptor substrate‐1 (IRS‐1). Fibroblasts, 3T3–F442A, were incubated at 37°C with 23 nM (500 ng/ml) human GH or 170 ng/ml insulin‐like growth factor I (IGF‐1) for the times indicated. Whole‐cell lysates were immunoprecipitated with antibodies to IRS‐1 (αIRS‐1), GH (αGH), or Janus kinase (αJAK2). The lane on the far right was loaded with one‐tenth of the volume of sample loaded in the other lanes. Immunoprecipitated proteins were immunoblotted (Blot) with antiphosphotyrosine antibody (αPY). Molecular weights (x 10−3) of protein standards are indicated. Tyrosyl phosphorylation of IRS‐1 increases rapidly and transiently in response GH (first six lanes), and IRS‐1 coprecipitates with a tyrosyl‐phosphorylated complex that comigrates with GH receptors and JAK2 (first four lanes) and vice versa (last four lanes), suggesting that it forms a complex with GH receptor and JAK2 in a GH‐dependent manner.

From , with permission
Figure 9. Figure 9.

Growth hormone receptor (GHR) signaling via insulin receptor substrate‐1 (IRS‐1) and IRS‐2. Solid molecules and arrows indicate signaling molecules and pathways regulated by GH. Dashed molecules and arrows indicate signaling proteins known to bind IRS‐1 and/or IRS‐2 via SH2 domain–mediated interactions (Nck, Grb‐2, fyn) in response to insulin, proteins with enzymatic activities that are stimulated by the action of phosphatidylinositol‐3′‐kinase (PI3K), or signaling pathways utilized in cells treated with insulin. These have not yet been shown to be involved in GH signal transduction. SHP2, SH2 domain containing tyrosine phosphatase; JAK, Janus kinase.

From , with permission
Figure 10. Figure 10.

Growth hormone (GH) stimulates a rapid, transient increase in diacylglycerol (DAG) in Ob1771 cells. Postconfluent Ob1771 cells maintained in standard medium were exposed to 5 nM GH (open squares) or 200 nM prostaglandin F2a (solid squares) for various times. Formation of DAG was measured. The basal value obtained in the absence of GH (3.5 nmol/1000 nmol of phospholipid) was subtracted from the reported values. Each value represents the mean of pooled triplicate wells (differences between determinations were < 20%). These results indicate that GH elicits a rapid, transient increase in DAG in Ob1771 cells.

From , with permission
Figure 11. Figure 11.

Growth hormone (GH) induces an increase in cytosolic Ca2+([Ca2+])i) in single INS‐1 cells. Changes in ([Ca2+]i were investigated in fura‐2‐loaded cells stimulated with 5 nM bovine GH (bGH) at 3 mM glucose in the absence (A) or presence (B) of 1 mM calciseptine. Cells were attached on glass coverslips and loaded with 1 mM fura‐2 acetoxymethyl ester for 30 min. [Ca2+]i was monitored by the measurement of 340:380 nm ratio during continuous perfusion with Krebs‐Ringer bicarbonate HEPES buffer containing 3 mM glucose as a basal condition. Stimuli were given through large‐orifice pipettes placed in the vicinity of the cell examined. Representative traces of those obtained in at least five cells are shown. These results demonstrate that GH induces a transient rise in intracellular Ca2+ levels in INS‐1 cells. The observation that the GH‐induced increase in [Ca2+]i is blocked by calciseptine suggests that, in these cells, GH activates voltage‐dependent, L‐type calcium channels.

From , with permission
Figure 12. Figure 12.

Growth hormone (GH), leukemia‐inhibitory factor (LIF), and interferon‐γ (IFNγ) induce tyrosyl phosphorylation of Stat1, Stat3, and Stat5 in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated in the absence of hormone or with 23 nM (500 ng/ml) human GH, 25 ng/ml human LIF, or 10 ng/ml murine IFNγ, as indicated, for 15 min. Whole‐cell lysates were immunoprecipitated with antibodies to Stat1 (αStat1), Stat3 (αStat3), or Stat5 (αStat5), as indicated. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. Migrations of Stat1, Stat3, and Stat5 are indicated. Signals observed in response to GH indicate that GH stimulates tyrosyl phosphorylation of Stats 1, 3, and 5. The differences in relative signal intensities for GH, LIF, and IFNγ for each Stat suggest that the requirements for activation differ for each Stat protein.

From , with permission
Figure 13. Figure 13.

Growth hormone (GH) promotes tyrosyl phosphorylation of Stat5A and Stat5B in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated without hormone (‐) or with 23 nM (500 ng/ml) human GH (+) for 15 min. Stat5 proteins were immunoprecipitated with antibodies to Stat5A (αStat5A) or Stat5B (αStat5B). Immunoprecipitates (IP) were subjected to Western blot analysis using antiphosphotyrosine antibody (αPY), αStat5A, or αStat5B. Tyrosyl phosphorylation of both Stat5A and 5B was induced by GH, as evidenced by the increased signal observed in lanes B and D compared to lanes A and C. Multiple Stat bands exist even in the absence of GH (lane E), suggesting the presence of multiple serine or threonine phosphorylation states.

From , with permission
Figure 14. Figure 14.

Growth hormone (GH)–induced Sis‐inducible element (SIE)–binding complex contains Stat1 and Stat3. An electrophoretic mobility shift assay was performed using the human SIE probe and nuclear extracts prepared from 3T3–F442A cells stimulated for 30 min with vehicle (control, lane 1), GH (500 ng/ml, lanes 2–4), leukemia‐inhibitory factor (LIF; 65 ng/ml, lanes 5–7), or interferon‐γ (IFNγ, 10 ng/ml, lanes 8–10). Nuclear extracts were preincubated for 20 min at room temperature with antibodies to Stat1 (αStat1; lanes 3, 6, and 9) or Stat3 (αStat3; lanes 5, 7, and 10). Nuclear extracts were then incubated with the radiolabeled DNA probe and subjected to electrophoresis. The detection of three bands in lane 2 (bands A, B, and C) and the observation that these bands can be supershifted with antibodies to Stats 1 and 3 indicate that GH induces binding of Stat1‐and Stat3‐containing complexes to the SIE.

From , with permission
Figure 15. Figure 15.

Serum response element (SRE) mediates induction of c‐fos by growth hormone (GH). Cells (NIH‐3T3) were transiently transfected with fos promoter plasmids and the α‐globin expression plasmid to indicate transfection efficiency. At 64 h after transfection, quiescent cells were stimulated with GH (500 ng/ml), 10% calf serum (CS), or vehicle (C, control) for 30 min. Total RNA was analyzed by ribonuclease protection assay. Positions of the protected fragments representing the human c‐fos reporter (upper arrow), α‐globin (middle arrow), and endogenous mouse c‐fos (lower arrow) transcripts are indicated. Hela cell RNA (H) provides a reference for the human c‐fos transcripts. A: Stimulation by GH of SRE‐FOS containing a single copy of the c‐fos SRE upstream of a human c‐fos reporter (from 222 bp upstream of the transcription start site through the coding region). B: Lack of induction of the reporter alone. C: Lack of induction of a mutant SRE‐FOS containing the reporter under control of a mutated SRE, which fails to bind serum response factor.

From , with permission


Figure 1.

Members of the cytokine receptor superfamily are schematically illustrated, including the specific receptors (R) for growth hormone (GH); prolactin (PRL); erythropoietin (EPO); granulocyte colony‐stimulating factor (G‐CSF); ciliary neurotrophic factor (CNTP); leukemia‐inhibitory factor (LIF); oncostatin M (OSM); leptin (Ob‐Rb); thrombopoietin (mpl); granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); interleukins (IL) 2–7, 9–13, and 15; and interferon (IFN)‐γ and‐α as well as shared receptor subunits including the IL‐3 receptor common β chain (Aic‐2/βc), the IL‐2 receptor common γ chain (γc), and gp 130. Conserved extracellular cysteine motifs are represented by four thin lines. Extracellular WSXWS motifs are represented by black boxes (a thinner box represents WSXWS‐like motifs with conservative substitutions). Numbered white boxes in the intracellular region represent the conserved Box 1 and Box 2 regions. Dotted lines indicate putative receptor complexes employed by ligand.

From , with permission


Figure 2.

Growth hormone (GH) increases tyrosyl phosphorylation of multiple cellular proteins in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were treated with or without 23 nM (500 ng/ml) GH for the indicated times at 37°C. Whole‐cell lysates were prepared, fractionated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes. The resulting blot was probed with antiphosphotyrosine antibody. Eleven novel tyrosyl‐phosphorylated bands are observed in response to GH, indicating that GH induces tyrosyl phosphorylation of multiple proteins.

From , with permission


Figure 3.

Growth hormone (GH) induces Janus kinase (JAK2) activity and tyrosyl phosphorylation. A: Cells, 3T3–F442A, were incubated at 25°C in the absence (lane A) or presence (lanes B–D) of 30 ng/ml human GH for 1 h. Solubilized proteins were immunoprecipitated using anti‐JAK2 antibody, incubated with [γ – 32P] ATP, and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and autoradiography (lanes A and B). The presence of a dark band in lane B, but not in lane A, indicates that GH activates JAK2, as assessed by JAK2 autophosphorylation. Then, JAK2 was excised from the gel (lane B) and subjected to limited acid hydrolysis at 109°C for 1.25 h. Following partial purification on Dowex‐50, fractions containing O‐phosphoserine and O‐phosphothreonine (lane C) or O‐phosphotyrosine (lane D) were resolved by thin‐layer electrophoresis (pH 3.5). Migrations of O‐phosphoserine (P‐Ser), O‐phosphothreonine (P‐Thr), and O‐phosphotyrosine (P‐Tyr) standards are indicated by the dashed circles. Greater than 99% of the 32P incorporated into JAK2 in the in vitro kinase assay co‐migrated with O‐phosphotyrosine, indicating that JAK2 is a tyrosine kinase. B: Fibroblasts, 3T3–F442A, were incubated with the indicated concentrations of human GH for the times shown. Whole‐cell lysates were immunoprecipitated with antibody to JAK2. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. The GH‐dependent signal indicates that in intact cells JAK2 is tyrosyl‐phosphorylated in response to GH.

Part A from , with permission; part B from , with permission


Figure 4.

Growth hormone (GH) receptor. Potential N‐linked glycosylation sites (N) and the extracellular cysteines (C) with three pairs of linked disulfide bonds are noted. The transmembrane domain is shown in black. The ten tyrosines (Y) present in the cytoplasmic region of rat GH receptor are noted. The position of the WSXWS‐like motif is indicated by the striped box. Intracellular Box 1 (proline‐rich domain) and Box 2 are shown as gray boxes. Regions of the receptor required for various functions are indicated. MAP, mitogen‐activated protein; JAK, Janus kinase; IRS, insulin receptor substrate.

From , with permission


Figure 5.

Possible signaling pathways initiated by binding of growth hormone (GH) to its receptor are shown. Solid arrows indicate pathways regulated by GH. Dotted arrows indicate pathways utilized by other growth factors but not yet shown to be involved in GH‐dependent signal transduction or pathways with only limited data to support their existence. P, phosphorylated tyrosines; JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol‐3‐kinase; PC‐PLC, phosphocholine–phospholipase C; DAG, diacylglycerol; PKC, protein kinsase C; SOS, son of sevenless; MAPK, mitogen‐activated protein kinase; MEK, MAPK/ERK kinase; PLA2; phospholipase A2; SRF, serum response factor; TCF, ternary complex factor; SIE, Sis‐inducible element; SRE, serum response elements; AP1, activator protein‐1; GLE, interferon‐γ‐activated sequence–like element.

From , with permission


Figure 6.

Growth hormone (GH) activates extracellular signal–regulated kinases (ERKs) 1 and 2. Fibroblasts, 3T3–F442A, were incubated with 23 nM (500 ng/ml) human GH for the times indicated. Whole‐cell lysates were blotted with an antibody which detects only the active, doubly phosphorylated form of ERKs 1 and 2. The GH‐dependent signal observable by 5 min indicates that GH induces phosphorylation and activation of ERKs 1 and 2.



Figure 7.

Growth hormone receptor (GHR) signaling via the extracellular signal–regulated kinases (ERKs) 1 and 2. A signaling cascade leading from GHR to the mitogen‐activated protein (MAP) kinase and activation of subsequent targets is shown. Solid arrows and signaling molecules and bold targets indicate pathways and proteins regulated by GH. Dotted arrows and targets in medium type indicate pathways, feedback mechanisms, and targets utilized in cells treated with other cytokines and growth factors that activate MAP kinase or are detected in vitro. These have not yet been shown to be involved in GH signal transduction. PLC, phospholipase C; PLA2, phospholipase A2; TCF, ternary complex factor; JAK, Janus kinase; GTP, guanosine triphosphate; Sos, son of sevenless; MEK, MAP kinase/ERK kinase. TAL, T‐cell acute lymphoblastic leukemia gene; NF, nuclear factor IL‐6; ATF, activating transcription factor‐2; MAPKAP, MAP kinase activated protein kinase‐2.



Figure 8.

Growth hormone (GH) promotes tyrosyl phosphorylation of insulin receptor substrate‐1 (IRS‐1). Fibroblasts, 3T3–F442A, were incubated at 37°C with 23 nM (500 ng/ml) human GH or 170 ng/ml insulin‐like growth factor I (IGF‐1) for the times indicated. Whole‐cell lysates were immunoprecipitated with antibodies to IRS‐1 (αIRS‐1), GH (αGH), or Janus kinase (αJAK2). The lane on the far right was loaded with one‐tenth of the volume of sample loaded in the other lanes. Immunoprecipitated proteins were immunoblotted (Blot) with antiphosphotyrosine antibody (αPY). Molecular weights (x 10−3) of protein standards are indicated. Tyrosyl phosphorylation of IRS‐1 increases rapidly and transiently in response GH (first six lanes), and IRS‐1 coprecipitates with a tyrosyl‐phosphorylated complex that comigrates with GH receptors and JAK2 (first four lanes) and vice versa (last four lanes), suggesting that it forms a complex with GH receptor and JAK2 in a GH‐dependent manner.

From , with permission


Figure 9.

Growth hormone receptor (GHR) signaling via insulin receptor substrate‐1 (IRS‐1) and IRS‐2. Solid molecules and arrows indicate signaling molecules and pathways regulated by GH. Dashed molecules and arrows indicate signaling proteins known to bind IRS‐1 and/or IRS‐2 via SH2 domain–mediated interactions (Nck, Grb‐2, fyn) in response to insulin, proteins with enzymatic activities that are stimulated by the action of phosphatidylinositol‐3′‐kinase (PI3K), or signaling pathways utilized in cells treated with insulin. These have not yet been shown to be involved in GH signal transduction. SHP2, SH2 domain containing tyrosine phosphatase; JAK, Janus kinase.

From , with permission


Figure 10.

Growth hormone (GH) stimulates a rapid, transient increase in diacylglycerol (DAG) in Ob1771 cells. Postconfluent Ob1771 cells maintained in standard medium were exposed to 5 nM GH (open squares) or 200 nM prostaglandin F2a (solid squares) for various times. Formation of DAG was measured. The basal value obtained in the absence of GH (3.5 nmol/1000 nmol of phospholipid) was subtracted from the reported values. Each value represents the mean of pooled triplicate wells (differences between determinations were < 20%). These results indicate that GH elicits a rapid, transient increase in DAG in Ob1771 cells.

From , with permission


Figure 11.

Growth hormone (GH) induces an increase in cytosolic Ca2+([Ca2+])i) in single INS‐1 cells. Changes in ([Ca2+]i were investigated in fura‐2‐loaded cells stimulated with 5 nM bovine GH (bGH) at 3 mM glucose in the absence (A) or presence (B) of 1 mM calciseptine. Cells were attached on glass coverslips and loaded with 1 mM fura‐2 acetoxymethyl ester for 30 min. [Ca2+]i was monitored by the measurement of 340:380 nm ratio during continuous perfusion with Krebs‐Ringer bicarbonate HEPES buffer containing 3 mM glucose as a basal condition. Stimuli were given through large‐orifice pipettes placed in the vicinity of the cell examined. Representative traces of those obtained in at least five cells are shown. These results demonstrate that GH induces a transient rise in intracellular Ca2+ levels in INS‐1 cells. The observation that the GH‐induced increase in [Ca2+]i is blocked by calciseptine suggests that, in these cells, GH activates voltage‐dependent, L‐type calcium channels.

From , with permission


Figure 12.

Growth hormone (GH), leukemia‐inhibitory factor (LIF), and interferon‐γ (IFNγ) induce tyrosyl phosphorylation of Stat1, Stat3, and Stat5 in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated in the absence of hormone or with 23 nM (500 ng/ml) human GH, 25 ng/ml human LIF, or 10 ng/ml murine IFNγ, as indicated, for 15 min. Whole‐cell lysates were immunoprecipitated with antibodies to Stat1 (αStat1), Stat3 (αStat3), or Stat5 (αStat5), as indicated. Immunoprecipitated proteins were subjected to Western blot analysis using antiphosphotyrosine antibody. Migrations of Stat1, Stat3, and Stat5 are indicated. Signals observed in response to GH indicate that GH stimulates tyrosyl phosphorylation of Stats 1, 3, and 5. The differences in relative signal intensities for GH, LIF, and IFNγ for each Stat suggest that the requirements for activation differ for each Stat protein.

From , with permission


Figure 13.

Growth hormone (GH) promotes tyrosyl phosphorylation of Stat5A and Stat5B in 3T3–F442A fibroblasts. 3T3–F442A fibroblasts were incubated without hormone (‐) or with 23 nM (500 ng/ml) human GH (+) for 15 min. Stat5 proteins were immunoprecipitated with antibodies to Stat5A (αStat5A) or Stat5B (αStat5B). Immunoprecipitates (IP) were subjected to Western blot analysis using antiphosphotyrosine antibody (αPY), αStat5A, or αStat5B. Tyrosyl phosphorylation of both Stat5A and 5B was induced by GH, as evidenced by the increased signal observed in lanes B and D compared to lanes A and C. Multiple Stat bands exist even in the absence of GH (lane E), suggesting the presence of multiple serine or threonine phosphorylation states.

From , with permission


Figure 14.

Growth hormone (GH)–induced Sis‐inducible element (SIE)–binding complex contains Stat1 and Stat3. An electrophoretic mobility shift assay was performed using the human SIE probe and nuclear extracts prepared from 3T3–F442A cells stimulated for 30 min with vehicle (control, lane 1), GH (500 ng/ml, lanes 2–4), leukemia‐inhibitory factor (LIF; 65 ng/ml, lanes 5–7), or interferon‐γ (IFNγ, 10 ng/ml, lanes 8–10). Nuclear extracts were preincubated for 20 min at room temperature with antibodies to Stat1 (αStat1; lanes 3, 6, and 9) or Stat3 (αStat3; lanes 5, 7, and 10). Nuclear extracts were then incubated with the radiolabeled DNA probe and subjected to electrophoresis. The detection of three bands in lane 2 (bands A, B, and C) and the observation that these bands can be supershifted with antibodies to Stats 1 and 3 indicate that GH induces binding of Stat1‐and Stat3‐containing complexes to the SIE.

From , with permission


Figure 15.

Serum response element (SRE) mediates induction of c‐fos by growth hormone (GH). Cells (NIH‐3T3) were transiently transfected with fos promoter plasmids and the α‐globin expression plasmid to indicate transfection efficiency. At 64 h after transfection, quiescent cells were stimulated with GH (500 ng/ml), 10% calf serum (CS), or vehicle (C, control) for 30 min. Total RNA was analyzed by ribonuclease protection assay. Positions of the protected fragments representing the human c‐fos reporter (upper arrow), α‐globin (middle arrow), and endogenous mouse c‐fos (lower arrow) transcripts are indicated. Hela cell RNA (H) provides a reference for the human c‐fos transcripts. A: Stimulation by GH of SRE‐FOS containing a single copy of the c‐fos SRE upstream of a human c‐fos reporter (from 222 bp upstream of the transcription start site through the coding region). B: Lack of induction of the reporter alone. C: Lack of induction of a mutant SRE‐FOS containing the reporter under control of a mutated SRE, which fails to bind serum response factor.

From , with permission
References
 1. Adams, T. E., L. Baker, R. J. Fiddes, and M. R. Brandon. The sheep growth hormone receptor: molecular cloning and ontogeny of mRNA expression in the liver. Mot. Cell. Endocrinol. 73: 135–145, 1990.
 2. Aguet, M., Z. Dembic, and G. Merlin. Molecular cloning and expression of the human interferon‐gamma receptor. Cell 55: 273–280, 1988.
 3. Amselem, S., P. Duquesnoy, O. Attree, G. Novelli, S. Bousnina, M. C. Postel‐Vinay, and M. Goossens. Laron dwarfism and mutations of the growth hormone‐receptor gene. N. Engl. J. Med. 321: 989–995, 1989.
 4. Amselem, S., M. L. Sobrier, P. Duquesnoy, R. Rappaport, M. C. Postel‐Vinay, M. Gourmelen, B. Dallapiccola, and M. Goossens. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. J. Clin. Invest. 87: 1098–1102, 1991.
 5. Anderson, N. G. Growth hormone activates mitogen‐activated protein kinase and S6 kinase and promotes intracellular tyrosine phosphorylation in 3T3–F442A preadipocytes. Biochem. J. 284: 649–652, 1992.
 6. Anderson, N. G. Simultaneous activation of p90RSK and p70S6K S6 kinases by growth hormone in 3T3–F442A preadipocytes. Biochem. Biophys. Res. Commun. 193: 284–290, 1993.
 7. Argetsinger, L. S., N. Billestrup, G. Norstedt, M. F. White, and C. Carter‐Su. Growth hormone, interferon‐gamma, and leukemia inhibitory factor utilize insulin receptor substrate‐2 in intracellular signaling. J. Biol. Chem. 271: 29415–29421, 1996.
 8. Argetsinger, L. S., G. S. Campbell, X. Yang, B. A. Witthuhn, O. Silvennoinen, J. N. Ihle, and C. Carter‐Su. Identification of JAK2 as a growth hormone receptor‐associated tyrosine kinase. Cell 74: 237–244, 1993.
 9. Argetsinger, L. S., and C. Carter‐Su. Mechanism of signaling by growth hormone receptor. Physiol. Rev. 76: 1089–1107, 1996.
 10. Argetsinger, L. S., G. W. Hsu, M. G. Myers, Jr., N. Billestrup, G. Norstedt, M. F. White, and C. Carter‐Su. Growth hormone, interferon‐gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate‐1. J. Biol. Chem. 270: 14685–14692, 1995.
 11. Asplin, C. M., A. C. Faria, E. C. Carlsen, V. A. Vaccaro, R. E. Barr, A. Iranmanesh, M. M. Lee, J. D. Veldhuis, and W. S. Evans. Alterations in the pulsatile mode of growth hormone release in men and women with insulin‐dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 69: 239–245, 1989.
 12. Bacon, C. M., D. W. McVicar, J. R. Ortaldo, R. C. Rees, J. J. O'Shea, and J. A. Johnston. Interleukin 12 (IL‐12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL‐2 and IL‐12. J. Exp. Med. 181: 399–404, 1995.
 13. Barcellini‐Couget, S., A. Pradines‐Figueres, P. Roux, C. Dani, and G. Ailhaud. The regulation by growth hormone of lipoprotein lipase gene expression is mediated by c‐fos protooncogene. Endocrinology 132: 53–60, 1993.
 14. Baumann, H., A. J. Symes, M. R. Comeau, K. K. Morella, Y. Wang, D. Friend, S. F. Ziegler, J. S. Fink, and D. P. Gearing. Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells. Mol. Cell. Biol. 14: 138–146, 1994.
 15. Baumgartner, J. W., C. A. Wells, C.‐M. Chen, and M. J. Waters. The role of the WSXWS equivalent motif in growth hormone receptor function. J. Biol. Chem. 269: 29094–29101, 1994.
 16. Baxter, R. C., and Z. Zaltsman. Induction of hepatic receptors for growth hormone (GH) and prolactin by GH infusion is sex independent. Endocrinology 115: 2009–2014, 1984.
 17. Bazan, J. F. A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL‐6 receptors, and the p75 IL‐2 receptor B‐chain. Biochem. Biophys. Res. Commun. 164: 788–795, 1989.
 18. Bazan, J. F. Haemopoietic receptors and helical cytokines. Immunol. Today 11: 350–354, 1990.
 19. Beadling, C., J. Ng, J. W. Babbage, and D. A. Cantrell. Interleukin‐2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J. 15: 1902–1913, 1996.
 20. Berczi, I., E. Nagy, S. De Toledo, R. Matusik, and H. Friesen. Pituitary hormones regulate c‐myc and DNA sythesis in lymphoid tissue. J. Immunol. 146: 2201–2206, 1991.
 21. Bergad, P. L., H.‐M. Shih, H. C. Towle, S. J. Schwarzenberg, and S. A. Berry. Growth hormone induction of hepatic serine protease inhibitor 2.1 transcription is mediated by a Stat5‐related factor binding synergistically to two gamma‐activated sites. J. Biol. Chem. 270: 24903–24910, 1995.
 22. Berger, L. C., T. S. Hawley, J. A. Lust, S. J. Goldman, and R. G. Hawley. Tyrosine phosphorylation of JAK‐TYK kinases in malignant plasma cell lines growth‐stimulated by interleukins 6 and 11. Biochem. Biophys. Res. Commun. 202: 596–605, 1994.
 23. Berlanga, J. J., O. Gualillo, H. Buteau, M. Applanat, P. A. Kelly, and M. Edery. Prolactin activates tyrosyl phosphorylation of insulin receptor substrate 1 and phosphatidylinositol‐3‐OH kinase. J. Biol. Chem. 272: 2050–2052, 1997.
 24. Bichell, D. P., K. Kikuchi, and P. Rotwein. Growth hormone rapidly activates insulin‐like growth factor I gene transcription in vivo. Mol. Endocrinol. 6: 1899–1908, 1992.
 25. Billestrup, N., G. Allevato, G. Norstedt, A. Moldrup, J. H. Nielsen, and A. Moldrup. Identification of intracellular domains in the growth hormone receptor involved in signal transduction. Proc. Soc. Exp. Biol. Med. 206: 205–209, 1994.
 26. Billestrup, N., P. Bouchelouche, G. Allevato, M. Hondo, and J. H. Nielsen. Growth hormone receptor C‐terminal domains required for growth hormone‐induced intracellular free Ca2+ oscillations and gene transcription. Proc. Natl. Acad. Sci. USA 92: 2725–2729, 1995.
 27. Billestrup, N., and J. M. Martin. Growth hormone binding to specific receptors stimulates growth and function of cloned insulin‐producing rat insulinoma RIN‐5AH cells. Endocrinology 116: 1175–1181, 1985.
 28. Billestrup, N., A. Moldrup, P. Serup, L. S. Mathews, G. Norstedt, and J. H. Nielsen. Introduction of exogenous growth hormone receptors augments growth hormone‐responsive insulin biosynthesis in rat insulinoma cells. Proc. Natl. Acad. Sci. USA 87: 7210–7214, 1990.
 29. Boisclair, Y. R., D. Seto, S. Hsieh, K. R. Hurst, and G. T. Ooi. Organization and chromosomal localization of the gene encoding the mouse acid labile subunit of the insulin‐like growth factor binding complex. Proc. Natl. Acad. Sci. USA 93: 10028–10033, 1996.
 30. Boutin, J.‐M., C. Jolicoeur, H. Okamura, J. Gagnon, M. Edery, M. Shirota, D. Banville, I. Dusanter‐Fourt, J. Djiane, and P. A. Kelly. Cloning and expression of the rat prolactin receptor, a member of the growth hormone/prolactin receptor gene family. Cell 53: 69–77, 1988.
 31. Burnside, J., S. S. Liou, and L. A. Cogburn. Molecular cloning of the chicken growth hormone receptor complementary deoxyribonucleic acid: mutation of the gene in sex‐linked dwarf chickens. Endocrinology 128: 3183–3192, 1991.
 32. Campbell, G. S., L. S. Argetsinger, J. N. Ihle, P. A. Kelly, J. A. Rillema, and C. Carter‐Su. Activation of JAK2 tyrosine kinase by prolactin receptors in Nb2 cells and mouse mammary gland explants. Proc. Natl. Acad. Sci. USA 91: 5232–5236, 1994.
 33. Campbell, G. S., L. J. Christian, and C. Carter‐Su. Evidence for involvement of the growth hormone receptor‐associated tyrosine kinase in actions of growth hormone. J. Biol. Chem. 268: 7427–7434, 1993.
 34. Campbell, G. S., D. J. Meyer, R. Raz, D. E. Levy, J. Schwartz, and C. Carter‐Su. Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. J. Biol. Chem. 270: 3974–3979, 1995.
 35. Campbell, G. S., T. Miyasaka, L. Pang, A. R. Saltiel, and C. Carter‐Su. Stimulation by growth hormone of MAP kinase activity in 3T3–F442A fibroblasts. J. Biol. Chem. 267: 6074–6080, 1992.
 36. Carter‐Su, C., A. P. J. King, L. S. Smit, J. A. VanderKuur, L. S. Argetsinger, G. S. Campbell, and W.‐H. Huo. Molecular mechanisms of growth hormone action. J. Anim. Sci. 75: 1–10, 1997.
 37. Carter‐Su, C., F. A. Rozsa, X. Wang, and J. R. Stubbart. Rapid and transitory stimulation of 3‐O‐methylglucose transport by growth hormone. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E723–E729, 1988.
 38. Carter‐Su, C., J. R. Stubbart, X. Wang, S. E. Stred, L. S. Argetsinger, and J. A. Shafer. Phosphorylation of highly purified growth hormone receptors by a growth hormone receptor‐associated tyrosine kinase. J. Biol. Chem. 264: 18654–18661, 1989.
 39. Catalioto, R. M., G. Ailhaud, and R. Negrel. Diacylglycerol production induced by growth hormone in Ob1771 preadipocytes arises from phosphatidylcholine breakdown. Biochem. Biophys. Res. Commun. 173: 840–848, 1990.
 40. Ceresa, B. P., and J. E. Pessin. Insulin stimulates the serine phosphorylation of the signal transducer and activator of transcription (STAT3) isoform. J. Biol. Chem. 271: 12121–12124, 1996.
 41. Cheatham, B., C.J. Vlahos, L. Cheatham, L. Wang, J. Blenis, and C. R. Kahn. Phosphatidylinositol 3–kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14: 4902–4911, 1994.
 42. Chen, C. M., R. W. Clarkson, Y. Xie, D. A. Hume, and M. J. Waters. Growth hormone and CSF‐1 share multiple response elements in the c‐fos promoter. Endocrinology 136: 4505–4516, 1995.
 43. Cherniack, A. D., J. K. Klarlund, B. R. Conway, and M. P. Czech. Disassembly of Son‐of‐sevenless proteins from Grb2 during p21ras desensitization by insulin. J. Biol. Chem. 270: 1485–1488, 1995.
 44. Chow, J. C., P. R. Ling, Z. Qu, L. Laviola, A. Ciccarone, B. R. Bistrian, and R. J. Smith. Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate‐1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. Endocrinology 137: 2880–2886, 1996.
 45. Chua, A. O., R. Chizzonite, B. B. Desai, T. P. Truitt, P. Nunes, L. J. Minetti, R. R. Warrier, D. H. Presky, J. F. Levine, M. K. Gately, and U. Gubler. Expression cloning of a human IL‐12 receptor component. J. Immunol. 153: 128–136, 1994.
 46. Cioffi, J. A., X. Wang, and J. J. Kopchick. Porcine growth hormone receptor cDNA sequence. Nucleic Acids Res. 18: 6451, 1990.
 47. Clarkson, R. W. E., C. M. Chen, S. Harrison, C. Wells, G. E. O. Muscat, and M. J. Waters. Early responses of trans‐activatingfactors to growth hormone in preadipocytes: differential regulation of CCAAT enhancer‐binding protein‐beta (C/EBPbeta) and C/EBPgamma. Mol. Endocrionol. 9: 108–120, 1995.
 48. Cobb, M. H., and E. J. Goldsmith. How MAP kinases are regulated. J. Biol. Chem. 270: 14843–14846, 1995.
 49. Colosi, P., K. Wong, S. R. Leong, and W. I. Wood. Mutational analysis of the intracellular domain of the human growth hormone receptor. J. Biol. Chem. 268: 12617–12623, 1993.
 50. Corbalan‐Garcia, S., S. S. Yang, K. R. Degenhardt, and D. Bar‐Sagi. Identification of the mitogen‐activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Mol. Cell. Biol. 16: 5674–5682, 1996.
 51. Crews, C. M., and R. L. Erikson. Extracellular signals and reversible protein phosphorylation: what to MEK of it all. Cell 74: 215–217, 1993.
 52. Cunningham, B. C., M. Ultsch, A. M. de Vos, M. G. Mulkerrin, K. R. Clauser, and J. A. Wells. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254: 821–825, 1991.
 53. Cunningham, B. C., and J. A. Wells. Rational design of receptor‐specific variants of human growth hormone. Proc. Natl. Acad. Sci. USA 88: 3407–3411, 1991.
 54. Curran, T., and B. R. Franza, Jr. Fos and Jun: the AP‐1 connection. Cell 55: 395–397, 1988.
 55. Dai, J., C. D. Scott, and R. C. Baxter. Regulation of the acid‐labile subunit of the insulin‐like growth factor complex in cultured rat hepatocytes. Endocrinology 135: 1066–1072, 1994.
 56. Damen, J. E., H. Wakao, A. Miyajima, J. Krosl, R. K. Humphries, R. L. Cutler, and G. Krystal. Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin‐induced cell proliferation and Stat5 activation. EMBO J. 14: 5557–5568, 1995.
 57. D'Andrea, A. D., G. D. Asman, and H. F. Lodish. Erythropoietin receptor and interleukin‐2 receptor B chain: a new receptor family. Cell 58: 1023–1024, 1989.
 58. Darnell, J. E., Jr., I. M. Kerr, and G. R. Stark. Jak‐STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421, 1994.
 59. DaSilva, L., O. M. Z. Howard, H. Rui, R. A. Kirken, and W. L. Farrar. Growth signaling and JAK2 association mediated by membrane‐proximal cytoplasmic regions of prolactin receptors. J. Biol Chem. 269: 18267–18270, 1994.
 60. Daughaday, W. H., K. Hall, M. S. Raben, W. D. Salmon, J. L. Van den Brande, and J. J. Van Wyk. Somatomedin: proposed designation for sulphation factor. Nature 235: 107, 1972.
 61. David, M., E. Petricoin III, C. Benjamin, R. Pine, M. J. Weber, and A. C. Larner. Requirement for MAP kinase (ERK2) activity in interferon alpha‐and interferon beta‐stimulated gene expression through STAT proteins. Science 269: 1721–1723, 1995.
 62. Davidson, M. B. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr. Rev. 8: 115–131, 1987.
 63. Davis, S., T. H. Aldrich, D. M. Valenzuela, V. Wong, M. E. Furth, S. P. Squinto, and G. D. Yancopoulos. The receptor for ciliary neurotrophic factor. Science 253: 59–63, 1991.
 64. Dekker, L. V., and P. J. Parker. Protein kinase C—a question of specificity. Trends Biochem. Sci. 19: 73–77, 1994.
 65. deVos, A. M., M. Ultsch, and A. A. Kossiakoff. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255: 306–312, 1992.
 66. Distel, R., H. S. Ro, B. S. Rosen, D. Groves, and B. M. Spiegelman. Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c‐fos. Cell 49: 835–844, 1987.
 67. Doglio, A., C. Dani, G. Fredrikson, P. Grimaldi, and G. Ailhaud. Acute regulation of insulin‐like growth factor‐I gene expression by growth hormone during adipose cell differentiation. EMBO J. 6: 4011–4016, 1987.
 68. Doglio, A., C. Dani, P. Grimaldi, and G. Ailhaud. Growth hormone regulation of the expression of differentiation‐dependent genes in preadipocyte Ob1771 cells. Biochem. J. 238: 123–129, 1986.
 69. Doglio, A., C. Dani, P. Grimaldi, and G. Ailhaud. Growth hormone stimulates c‐fos gene expression by means of protein kinase C without increasing inositol lipid turnover. Proc. Natl. Acad. Sci. USA 86: 1148–1152, 1989.
 70. Domene, H., K. Krishnamurthi, R. Eshet, I. Gilad, Z. Laron, I. Koch, B. Stannard, F. Cassorla, C. T. Roberts, Jr., and D. LeRoith. Growth hormone (GH) stimulates insulin‐like growth factor‐I (IGF‐I) and IGF‐I‐binding protein‐3, but not GH receptor gene expression in livers of juvenile rats. Endocrinology 133: 675–682, 1993.
 71. Drachman, J. G., J. D. Griffin, and K. Kaushansky. The c‐Mp1 ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c‐Mpl. J. Biol. Chem. 270: 4979–4982, 1995.
 72. Duriez, B., M. L. Sobrier, P. Duquesnoy, M. Tixier‐Boichard, E. Decuypere, G. Coquerelle, M. Zeman, M. Goossens, and S. Amselem. A naturally occurring growth hormone receptor mutation: in vivo and in vitro evidence for the functional importance of the WS motif common to all members of the cytokine receptor superfamily. Mol. Endocrinol. 7: 806–814, 1993.
 73. Eden, S., J. Schwartz, and J. L. Kostyo. Effects of preincubation on the ability of rat adipocytes to bind and respond to growth hormone. Endocrinology 111: 1505–1512, 1982.
 74. Eilers, A., D. Georgellis, B. Klose, C. Schindler, A. Ziemiecki, A. G. Harpur, A. F. Wilks, and T. Decker. Differentiation‐regulated serine phosphorylation of STAT1 promotes GAF activation in macrophages. Mol. Cell. Biol. 15: 3579–3586, 1995.
 75. Ekberg, S., L. Carlsson, B. Carlsson, H. Billig, and J. Jansson. Plasma growth hormone pattern regulates epidermal growth factor (EGF) receptor messenger ribonucleic acid levels and EGF binding in the rat liver. Endocrinology 25: 2158–2166, 1989.
 76. Emtner, M., L. S. Mathews, and G. Norstedt. Growth hormone (GH) stimulates protein synthesis in cells transfected with GH receptor complementary DNA. Mol. Endocrinol. 4: 2014–2020, 1990.
 77. Enberg, B., A. Hulthen, C. Moller, G. Norstedt, and S. M. Francis. Growth hormone (GH) regulation of a rat serine protease inhibitor fusion gene in cells transfected with GH receptor DNA. J. Mol. Endocrinol. 12: 39–46, 1994.
 78. Eriksson, H., R. Sundler, and J. Donner. Growth hormone increases phosphoinositide turnover in rat adipocytes that are sensitive to the insulin‐like action of the hormone. Mol. Cell. Biochem. 97: 181–186, 1990.
 79. Fan, G., and J. A. Rillema. Prolactin stimulation of protein kinase C in isolated mouse mammary gland nuclei. Harm. Metab. Res. 25: 564–568, 1993.
 80. Feng, J., B. A. Witthuhn, T. Matsuda, F. Kohlhuber, I. M. Kerr, and J. N. Ihle. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell. Biol. 17: 2497–2501, 1997.
 81. Firmbach‐Kraft, I., M. Byers, T. Shows, R. Dalla‐Favera, and J. J. Krolewski. tyk2, prototype of a novel class of non‐receptor tyrosine kinase genes. Oncogene 5: 1329–1336, 1990.
 82. Foster, C. M., J. A. Shafer, F. W. Rozsa, X. Wang, S. D. Lewis, D. A. Renken, J. E. Natale, J. Schwartz, and C. Carter‐Su. Growth hormone promoted tyrosyl phosphorylation of growth hormone receptors in murine 3T3–F442A fibroblasts and adipocytes. Biochemistry 27: 326–334, 1988.
 83. Fourcin, M., S. Chevalier, J.‐J. Lebrun, P. Kelly, A. Pouplard, J. Wijdenes, and H. Gascan. Involvement of gp130/interleukin‐6 receptor transducing component in interleukin‐11 receptor. Eur. J. Immunol., 24: 277–280, 1994.
 84. Frank, S. J., G. Gilliland, A. S. Kraft, and C. S. Arnold. Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase. Endocrinology 135: 2228–2239, 1994.
 85. Frank, S. J., Y. Woelsung, Y. Zhao, J. F. Goldsmith, G. Gilliland, J. Jiang, I. Sakai, and A. S. Kraft. Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. J. Biol. Chem. 270: 14776–14785, 1995.
 86. Franza, B. R., F. J. Rauscher, S. F. Josephs, and T. Curran. The fos complex and fos‐related antigens recognize sequence elements that contain AP‐1 binding sites. Science 239: 1150–1153, 1988.
 87. Frattali, A. L., J. L. Treadway, and J. E. Pessin. Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular beta subunit trans‐ and cis‐autophosphorylation and substrate kinase activation. J. Biol. Chem. 267: 19521–19528, 1992.
 88. Fu, X.‐Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha‐induced cytoplasmic protein tyrosine kinase(s). Cell 70: 323–335, 1992.
 89. Fuh, G., B. C. Cunningham, R. Fukunaga, S. Nagata, D. V. Goeddel, and J. A. Wells. Rational design of potent antagonists to the human growth hormone receptor. Science 256: 1677–1680, 1992.
 90. Fuh, G., M. G. Mulkerrin, S. Bass, N. McFarland, M. Brochier, J. H. Bourell, D. R. Light, and J. A. Wells. The human growth hormone receptor. Secretion from Escherichia coli and disulfide bonding pattern of the extracellular binding domain. J. Biol. Chem. 265: 3111–3115, 1990.
 91. Fujii, H., Y. Nakagawa, U. Schindler, A. Kawahara, H. Mori, F. Gouilleux, B. Groner, J. N. Ihle, Y. Minami, T. Miyazaki, and T. Taniguchi. Activation of Stat5 by interleukin 2 requires a carboxyl‐terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transduction. Proc. Natl. Acad. Sci. USA 92: 5482–5486, 1995.
 92. Fukunaga, R., E. Ishizaka‐Ikeda, and S. Nagata. Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony‐stimulating factor receptor. Cell 74: 1079–1087, 1993.
 93. Fukunaga, R., E. Ishizaka‐Ikeda, Y. Seto, and S. Nagata. Expression cloning of a receptor for murine granulocyte colony‐stimulating factor. Cell 61: 341–350, 1990.
 94. Galsgaard, E. D., F. Gouilleux, B. Groner, P. Serup, J. H. Nielsen, and N. Billestrup. Identification of a growth hormone‐responsive STAT5–binding element in the rat insulin 1 gene. Mol. Endocrinol. 10: 652–660, 1996.
 95. Gaur, S., H. Yamaguchi, and H. M. Goodman. Growth hormone increases calcium uptake in rat fat cells by a mechanism dependent on protein kinase C. Am. J. Physiol. 270 (Cell Physiol. 39): C1485–C1492, 1996.
 96. Gaur, S., H. Yamaguchi, and H. M. Goodman. Growth hormone regulates cytosolic free calcium in rat fat cells by maintaining L‐type calcium channels. Am. J. Physiol. 270 (Cell Physiol. 39): C1478–C1484, 1996.
 97. Gause, I., and S. Eden. Induction of growth hormone (GH) receptors in adipocytes of hypophysectomized rats by GH. Endocrinology 118: 119–124, 1986.
 98. Gearing, D. P., M. R. Comeau, D. J. Friend, S. D. Gimpel, C. J. Thut, J. McGourty, K. K. Brasher, J. A. King, S. Gillis, and B. Mosley. The IL‐6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science 255: 1434–1437, 1992.
 99. Gearing, D. P., J. A. King, N. M. Gough, and N. A. Nicola. Expression cloning of a receptor for human granulocyte‐macrophage colony‐stimulating factor. EMBO J. 8: 3667–3676, 1989.
 100. Gearing, D. P., C. J. Thut, T. VandenBos, S. D. Gimpel, P. B. Delaney, J. King, V. Price, D. Cosman, and P. M. Beckmann. Leukemia inhibitory factor receptor is structurally related to the IL‐6 signal transducer, gp130. EMBO J. 10: 2839–2848, 1991.
 101. Gerhartz, C., B. Heesel, J. Sasse, U. Hemmann, C. Landgraf, J. Schneider‐Mergener, F. Horn, P. C. Heinrich, and L. Graeve. Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation. J. Biol. Chem. 271: 12991–12998, 1996.
 102. Ghilardi, N., and R. C. Skoda. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor‐dependent cell line. Mol. Endocrinol. 11: 393–399, 1997.
 103. Gille, H., M. Kortenjann, O. Thomae, C. Moomaw, C. Slaughter, M. H. Cobb, and P. E. Shaw. ERK phosphorylation potentiates Elk‐1‐mediated ternary complex formation and transactivation. EMBO J. 14: 951–962, 1995.
 104. Giri, J. G., M. Ahdieh, J. Eisenman, K. Shanebeck, K. Grabstein, S. Kumaki, A. Namen, L. S. Park, D. Cosman, and D. Anderson. Utilization of the beta and gamma chains of the IL‐2 receptor by the novel cytokine IL‐15. EMBO J. 13: 2822–2830, 1994.
 105. Godowski, P. J., D. W. Leung, L. R. Meacham, J. P. Galgani, R. Hellmiss, R. Keret, P. S. Rotwein, J. S. Parks, Z. Laron, and W. I. Wood. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron‐type dwarfism. Proc. Natl. Acad. Sci. USA 86: 8083–8087, 1989.
 106. Goldsmith, M. A., W. Xu, M. C. Amaral, E. S. Kuczek, and W. C. Greene. The cytoplasmic domain of the interleukin‐2 receptor beta chain contains both unique and functionally redundant signal transduction elements. J. Biol. Chem. 269: 14698–14704, 1994.
 107. Gomez, J., C. Pitton, A. Garcia, A. Martinez de Aragon, A. Silva, and A. Rebollo. The zeta isoform of protein kinase C controls interleukin‐2‐mediated proliferation in a murine T cell line: evidence for an additonal role of protein kinase C epsilon and beta. Exp. Cell. Res. 218: 105–113, 1995.
 108. Gong, T.‐W. L., D. J. Meyer, J. Liao, C. L. Hodge, G. S. Campbell, X. Wang, N. B. Billestrip, C. Carter‐Su, and J. Schwartz. Regulation of glucose transport and c‐fos and agrl expression in cells with mutated or endogenous growth hormone receptors. Endocrinology 139: 1863–1871, 1998
 109. Goodman, H. M. Effects of growth hormone on the penetration of l‐arabinose into adipose tissue. Endocrinology 78: 819–825, 1966.
 110. Goodwin, R. G., D. Firend, S. F. Ziegler, R. Jerzy, B. A. Falk, S. Simpel, D. Cosman, S. K. Dower, C. J. March, A. I. Namen, and L. S. Park. Cloning of the human and murine interleukin‐7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 60: 941–951, 1990.
 111. Gorin, E., and H. M. Goodman. Turnover of growth hormone receptors in rat adipocytes. Endocrinology 116: 1796–1805, 1985.
 112. Gorman, D. M., N. Itoh, T. Kitamura, J. Schreurs, S. Yonehara, I. Yahara, K. Arai, and A. Miyajima. Cloning and expression of a gene encoding an interleukin 3 receptor‐like protein: identification of another member of the cytokine receptor gene family. Proc. Natl. Acad. Sci. USA 87: 5459–5463, 1990.
 113. Gouilleux, F., C. Pallard, I. Dusanter‐Fourt, H. Wakao, L. A. Haldosen, G. Norstedt, D. Levy, and B. Groner. Prolactin, growth hormone, erythropoietin and granulocyte‐macrophage colony stimulating factor induce MGF‐Stat5 DNA binding activity. EMBO J. 14: 2005–2013, 1995.
 114. Gouilleux, F., H. Wakao, M. Mundt, and B. Groner. Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J. 13: 4361–4369, 1994.
 115. Goujon, L., G. Allevato, G. Simonin, L. Paquereau, A. Le Cam, J. Clark, J. H. Nielsen, J. Djiane, M. C. Postel‐Vinay, M. Edery, and P. A. Kelly. Cytoplasmic sequences of the growth hormone receptor necessary for signal transduction. Proc. Natl. Acad. Sci. USA 91: 957–961, 1994.
 116. Graham, R., and M. Z. Gilman. Distinct protein targets for signals acting at the c‐fos serum response element. Science 251: 189–192, 1991.
 117. Greenlund, A. C., M. A. Farrar, B. Viviano, and R. D. Schreiber. Ligand‐induced IFN‐gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 13: 1591–1600, 1994.
 118. Gronowski, A. M., and P. Rotwein. Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen‐activated protein kinase and Stat91. J. Biol. Chem. 269: 7874–7878, 1994.
 119. Gronowski, A. M., and P. Rotwein. Rapid changes in gene expression after in vivo growth hormone treatment. Endocrinology 136: 4741–4748, 1995.
 120. Gronowski, A. M., C. L. Stunff, and P. Rotwein. Acute nuclear actions of growth hormone (GH): cycloheximide inhibits inducible activator protein‐1 activity, but does not block GH‐regulated signal transducer and activator of transcription activation or gene expression. Endocrinology 137: 55–64, 1996.
 121. Gronowski, A.M., Z. Zhong, Z. Wen, M.J. Thomas, J. E. Darnell, Jr., and P. Rotwein. Nuclear actions of growth hormone: rapid tyrosine phosphorylation and activation of Stat1 and Stat3 after in vivo growth hormone treatment. Mol. Endocrinol. 9: 171–177, 1995.
 122. Guller, S., D. L. Allen, R. E. Corin, C. J. Lockwood, and M. Sonenberg. Growth hormone and fibronectin expression in 3T3 preadipose cells. Endocrinology 130: 2609–2616, 1992.
 123. Guller, S., R. E. Corin, K. Yuan‐Wu, and M. Sonenberg. Up‐regulation of vinculin expression in 3T3 preadipose cells by growth hormone. Endocrinology 129: 527–533, 1991.
 124. Gurland, G., G. Ashcom, B. H. Cochran, and J. Schwartz. Rapid events in growth hormone action. Induction of c‐fos and c‐jun transcription in 3T3–F442A preadipocytes. Endocrinology 127: 3187–3195, 1990.
 125. Hackett, R. H., Y. D. Wang, and A. C. Lamer. Mapping of the cytoplasmic domain of the human growth hormone receptor required for the activation of Jak2 and Stat proteins. J. Biol. Chem. 270: 21326–21330, 1995.
 126. Hall, L. J., Y. Kajimoto, D. Bichell, S. W. Kim, P. L. James, D. Counts, L. J. Nixon, G. Tobin, and P. Rotwein. Functional analysis of the rat insulin‐like growth factor I gene and identification of an IGF‐I gene promoter. DNA Cell Biol. 11: 301–313, 1992.
 127. Han, Y., D. W. Leaman, D. Watling, N. C. Rogers, B. Groner, I. M. Kerr, W. I. Wood, and G. R. Stark. Participation of JAK and STAT proteins in growth hormone‐induced signaling. J. Biol. Chem. 271: 5947–5952, 1996.
 128. Hansen, L. H., X. Wang, J. J. Kopchick, P. Bouchelouche, J. H. Nielsen, E. D. Galsgaard, and N. Billestrup. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation. J. Biol. Chem. 271: 12669–12673, 1996.
 129. Harding, P. A., X. Z. Wang, B. Kelder, S. Souza, S. Okada, and J. J. Kopchick. In vitro mutagenesis of growth hormone receptor Asn‐linked glycosylation sites. Mol. Cell. Endocrinol. 106: 171–180, 1994.
 130. Harpur, A. G., A.‐C. Andres, A. Ziemiecki, R. R. Aston, and A. F. Wilks. JAK2, a third member of the JAK family of protein tyrosine kinases. Oncogene 7: 1347–1353, 1992.
 131. Hatakeyama, M., M. Tsudo, S. Minamoto, T. Kono, T. Doi, T. Miyata, M. Miyasaka, and T. Taniguchi. Interleukin‐2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNAs. Science 244: 551–556, 1989.
 132. Hauser, S. D., M. F. McGrath, R. J. Collier, and G. G. Krivi. Cloning and in vivo expression of bovine growth hormone receptor mRNA. Mol. Cell. Endocrinol. 72: 187–200, 1990.
 133. He, T.‐C., N. Jiang, H. Zhuang, D. Quelle, and D. M. Wojchowski. The extended box 2 subdomain of erythropoietin receptor is nonessential for Jak2 activation yet critical for efficient mitogenesis in FDC‐ER cells. J. Biol. Chem. 269: 18291–18294, 1994.
 134. He, T. C., N. Jiang, H. Zhuang, and D. M. Wojchowski. Erythropoietin‐induced recruitment of Shc via a receptor phosphotyrosine‐independent, Jak2‐associated pathway. J. Biol. Chem. 270: 11055–11061, 1995.
 135. He, Y. W., and T. R. Malek. The IL‐2 receptor gamma c chain does not function as a subunit shared by the IL‐4 and IL‐13 receptors. Implication for the structure of the IL‐4 receptor. J. Immunol. 155: 9–12, 1995.
 136. Hemmi, S., R. Bohni, G. Stark, F. DiMarco, and M. Aguet. A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells. Cell 76: 803–810, 1994.
 137. Hershko, A., and A. Ciechanover. The ubiquitin system for protein degradation. Annu. Rev. Biochem. 61: 761–807, 1992.
 138. Hibi, M., M. Murakami, M. Saito, T. Hirano, T. Taga, and T. Kishimoto. Molecular cloning and expression of an IL‐6 signal transducer, gp130. Cell 63: 1149–1157, 1990.
 139. Hill, C. S., and R. Treisman. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 80: 199–211, 1995.
 140. Hilton, D. J., A. A. Hilton, A. Raicevic, S. Rakar, M. Harrison‐Smith, N. M. Gough, C. G. Begley, D. Metcalf, N. A. Nicola, and T. A. Willson. Cloning of a murine IL‐11 receptor alpha‐chain; requirement for gp130 for high affinity binding and signal transduction. EMBO J. 13: 4765–4775, 1994.
 141. Hilton, D. J., J. G. Zhang, D. Metcalf, W. S. Alexander, N. A. Nicola, and T. A. Willson. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc. Natl. Acad. Sci. USA 93: 497–501, 1996.
 142. Ho, A S Y., Y. Liu, T. Khan, D.‐H. Hsu, J. F. Bazan, and K. W. Moore. A receptor for interleukin 10 is related to interferon receptors. Proc. Natl. Acad. Sci. USA 90: 11267–11271, 1993.
 143. Ho, J. L., B. Zhu, S. He, B. Du, and R. Rothman. Interleukin 4 receptor signaling in human monocytes and U937 cells involves the activation of a phosphatidylcholine‐specific phospholipase C: a comparison with chemotactic peptide, FMLP, phospholipase D, and sphingomyelinase. J. Exp. Med. 180: 1457–1469, 1994.
 144. Hou, J., U. Schindler, W. J. Henzel, S. C. Wong, and S. L. McKnight. Identification and purification of human Stat proteins activated in response to interleukin‐2. Immunity 2: 321–329, 1995.
 145. Huang, N., L. A. Cogburn, S. K. Agarwal, H. L. Marks, and J. Burnside. Overexpression of a truncated growth hormone receptor in the sex‐linked dwarf chicken: evidence for a splice mutation. Mol. Endocrinol. 7: 1391–1398, 1993.
 146. Hug, H., and T. F. Sarre. Protein kinase C isoenzymes: divergence in signal transduction? Biochem. J. 291: 329–343, 1993.
 147. Ihle, J. N. STATs: signal transducers and activators of transcription. Cell 84: 331–334, 1996.
 148. Hondo, M. M., P. De Meyts, and P. Bouchelouche. Human growth hormone increases cytosolic free calcium in cultured human IM‐9 lymphocytes: a novel mechanism of growth hormone transmembrane signalling. Biochem. Biophys. Res. Commun. 202: 391–397, 1994.
 149. Ip, N. Y., S. H. Nye, T. G. Boulton, S. Davis, T. Taga, Y. Li, S. J. Birren, K. Yasukawa, T. Kishimoto, D. J. Anderson, N. Stahl, and G. D. Yancopoulos. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL‐6 transducing receptor component gp130. Cell 69: 1121–1132, 1992.
 150. Isgaard, J., C. Moller, OGP. Isaksson, A. Nilsson, L. S. Mathews, and G. Norstedt. Regulation of insulin‐like growth factor messenger ribonucleic acid in rat growth plate by growth hormone. Endocrinology 122: 1515–1520, 1988.
 151. Itoh, N., S. Yonehara, J. Schreurs, D. M. Gorman, K. Maruyama, A. Ishii, I. Yahara, K. Arai, and A. Miyajima. Cloning of an interleukin‐3 receptor gene: a member of a distinct receptor gene family. Science 247: 324–327, 1990.
 152. Janecht, R., W. H. Ernst, V. Pingoud, and A. Nordheim. Activation of ternary complex factor elk‐1 by MAP kinases. EMBO J. 12: 5097–5104, 1993.
 153. Jiang, N., T. C. He, A. Miyajima, and D. M. Wojchowski. The box 1 domain of the erythropoietin receptor specifies Janus kinase 2 activation and functions mitogenically within an interleukin 2 beta‐receptor chimera. J. Biol. Chem. 271: 16472–16476, 1996.
 154. Johnson, R. J. Diminution of pulsatile growth hormone secretion in the domestic fowl (Gallus domesticus): evidence of sexual dimorphism. J. Endocrinol. 119: 101–109, 1988.
 155. Johnson, R. M., M. A. Napier, M.J. Cronin, and K. L. King. Growth hormone stimulates the formation of sn‐1,2‐diacylglycerol in rat hepatocytes. Endocrinology 127: 2099–2103, 1990.
 156. Johnston, J. A., M. Kawamura, R. A. Kirken, Y.‐Q. Chen, T. B. Blake, K. Shibuya, J. R. Ortaldo, D. W. McVicar, and J. J. O'Shea. Phosphorylation and activation of the Jak‐3 Janus kinase in response to interleukin‐2. Nature 370: 151–153, 1994.
 157. Kazansky, A. V., B. Raught, S. M. Lindsey, Y.‐F. Wang, and J. M. Rosen. Regulation of mammary gland factor/Stat5a during mammary gland development. Mol. Endocrinol. 9: 1598–1609, 1995.
 158. Keegan, A. D., K. Nelms, M. White, L.‐M. Wang, J. H. Pierce, and W. E. Paul. An IL‐4 receptor region containing an insulin receptor motif is important for IL‐4‐mediated IRS‐1 phosphorylation and cell growth. Cell 76: 811–820, 1994.
 159. Kessler, D. S., S. A. Veals, X.‐Y. Fu, and D. E. Levy. Interferon‐alpha regulates nuclear translocation and DNA‐binding affinity of ISGF3, a multimeric transcriptional activator. Genes Dev. 4: 1753–1765, 1990.
 160. Kilgour, E., I. Gout, and N. G. Anderson. Requirement for phosphoinositide 3‐OH kinase in growth hormone signalling to the mitogen‐activated protein kinase and p70s6k pathways. Biochem J. 315: 517–522, 1996.
 161. Kim, S. W., R. Lajara, and P. Rotwein. Structure and function of a human insulin‐like growth factor‐I gene promoter. Mol. Endocrinol. 5: 1964–1972, 1991.
 162. Kitamura, T., N. Sato, K. Arai, and A. Miyajima. Expression cloning of the human IL‐3 receptor cDNA reveals a shared beta subunit for the human IL‐3 and GM‐CSF receptors. Cell 66: 1165–1174, 1991.
 163. Kordula, T., J. Ripperger, K. M. Morella, J. Travis, and H. Baumann. Two separate signal transducer and activator of transcription proteins regulate transcription of the serine proteinase inhibitor‐3 gene in hepatic cells. J. Biol. Chem. 271: 6752–6757, 1996.
 164. Kuhne, M. R., T. Pawson, G. E. Lienhard, and G.‐S. Feng. The insulin receptor substrate 1 associates with the SH2–containing phosphotyrosine phosphatase Syp. J. Biol. Chem. 268: 11479–11481, 1993.
 165. Lebrun, J.‐J., S. Ali, V. Goffin, A. Ullrich, and P. A. Kelly. A single phosphotyrosine residue of the prolactin receptor is responsible for activation of gene transcription. Proc. Natl. Acad. Sci. USA 2: 4031–4035, 1995.
 166. LeCam, A., G. Pages, P. Auberger, G. LeCam, P. Leopold, R. Benarous, and N. Glaichenhaus. Study of a growth hormone‐regulated protein secreted by rat hepatocytes: cDNA cloning, anti‐protease activity and regulation of its synthesis by various hormones. EMBO J. 6: 1225–1232, 1987.
 167. Lechleider, R. J., R. M. Freeman, Jr., and B. G. Neel. Tyrosyl phosphorylation and growth factor receptor association of the human corkscrew homologue, SH‐PTP2. J. Biol. Chem. 268: 13434–13438, 1993.
 168. Lee, C.‐H., W. Li, R. Nishimura, M. Zhou, A. G. Batzer, M. G. Myers, Jr., M. F. White, J. Schlessinger, and E. Y. Skolnik. Nck associates with the SH2 domain‐docking protein IRS‐1 in insulin‐stimulated cells. Proc. Natl. Acad. Sci. USA 90: 11713–11717, 1993.
 169. Legraverend, C., A. Mode, S. Westin, A. Strom, H. Eguchi, P. G. Zaphiropoulos, and J. Gustafsson. Transcriptional regulation of rat P‐450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion. Mol. Endocrinol. 6: 259–266, 1992.
 170. Leung, D. W., S. A. Spencer, G. Cachianes, R. G. Hammonds, C. Collins, W.J. Henzel, R. Barnard, M.J. Waters, and W.I. Wood. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 330: 537–543, 1987.
 171. Lin, J. X., J. Mietz, W. S. Modi, S. John, and W. J. Leonard. Cloning of human Stat5B. Reconstitution of interleukin‐2‐induced Stat5A and Stat5B DNA binding activity in COS‐7 cells. J. Biol. Chem. 271: 10738–10744, 1996.
 172. Liu, S.‐H., J.‐T. Ma, A. Y. Yueh, S. P. Lees‐Miller, C. W. Anderson, and S.‐Y. Ng. The carboxyl‐terminal transactivation domain of human serum response factor contains DNA‐activated protein kinase phosphorylation sites. J. Biol. Chem. 268: 21124–21154, 1993.
 173. Liu, X., G. W. Robinson, F. Gouilleux, B. Groner, and L. Hennighausen. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc. Natl. Acad. Sci. USA 92: 8831–8835, 1995.
 174. Liu, X., G. W. Robinson, and L. Hennighausen. Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation. Mol. Endocrinol. 10: 1496–1506, 1996.
 175. Lobie, P. E., G. Allevato, J. H. Nielsen, G. Norstedt, and N. Billestrup. Requirement of tyrosine residues 333 and 338 of the growth hormone (GH) receptor for selected GH stimulated function. J. Biol. Chem. 270: 21745–21750, 1995.
 176. Maloff, B. L., J. H. Levine, and D. H. Lockwood. Direct effects of growth hormone on insulin action in rat adipose tissue maintained in vitro. Endocrinology 107: 538–544, 1980.
 177. Marais, R. M., J. J. Hsuan, C. McGuigan, J. Wynne, and R. Treisman. Casein kinase II phosphorylation increases the rate of serum response factor‐binding site exchange. EMBO J. 11: 97–105, 1992.
 178. Marrero, I., A. K. Green, P. H. Cobbold, and C.J. Dixon. Bovine growth hormone induces oscillations in cytosolic free Ca2+ in single rat hepatocytes. Biochem. J. 313: 525–528, 1996.
 179. Marte, B. M., T. Meyer, S. Stabel, G. J. Standke, S. Jaken, D. Fabbro, and N. E. Hynes. Protein kinase C and mammary cell differentiation: involvement of protein kinase C alpha in the induction of beta‐casein expression. Cell Growth Differ. 5: 239–247, 1994.
 180. Martial, J. A., R. A. Hallewell, J. D. Baxter, and H. M. Goodman. Human growth hormone: complementary DNA cloning and expression in bacteria. Science 205: 602–607, 1979.
 181. Mathews, L. S., B. Enberg, and G. Norstedt. Regulation of rat growth hormone receptor gene expression. J. Biol. Chem. 264: 9905–9910, 1989.
 182. Mathews, L. S., G. Norstedt, and R. D. Palmiter. Regulation of insulin‐like growth factor I gene expression by growth hormone. Proc. Natl. Acad. Sci. USA 83: 9343–9347, 1986.
 183. Mendez, R., M. G. Myers, Jr., M. F. White, and R. E. Rhoads. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS‐I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3‐kinase. Mol. Cell. Biol. 16: 2857–2864, 1996.
 184. Meyer, D. J., G. S. Campbell, B. H. Cochran, L. S. Argetsinger, A. C. Larner, D. S. Finbloom, C. Carter‐Su, and J. Schwartz. Growth hormone induces a DNA binding factor related to the interferon‐stimulated 91kD transcription factor. J. Biol. Chem. 269: 4701–4704, 1994.
 185. Meyer, D. J., E. W. Stephenson, L. Johnson, B. H. Cochran, and J. Schwartz. The serum response element can mediate the induction of c‐fos by growth hormone. Proc. Natl. Acad. Sci. USA 90: 6721–6725, 1993.
 186. Minami, S., J. Kamegai, H. Sugihara, O. Hasegawa, and I. Wakabayashi. Systemic administration of recombinant human growth hormone induces expresssion of the c‐fos gene in the hypothalamic arcuate and periventricular nuclei in hypophy‐sectomized rats. Endocrinology 131: 247–253, 1992.
 187. Misra, R. P., V. M. Rivera, J. M. Wang, P.‐D. Fan, and M. E. Greenberg. The serum response factor is extensively modified by phosphorylation following its synthesis in serum‐stimulated fibroblasts. Mol. Cell. Biol. 11: 4545–4554, 1991.
 188. Miyazaki, T., M. Maruyama, G. Yamada, M. Hatakeyama, and T. Taniguchi. The integrity of the conserved “WS motif” common to IL‐2 and other cytokine receptors is essential for ligand binding and signal transduction. EMBO J. 10: 3191–3197, 1991.
 189. Moldrup, A., N. Billestrup, T. Dryberg, and J. H. Nielsen. Growth hormone action in rat insulinoma cells expressing truncated growth hormone receptors. J. Biol. Chem. 266: 17441–17445, 1991.
 190. Moller, C., M. Emtner, P. Arner, and G. Norstedt. Growth hormone regulation of lipid metabolism in cells transfected with growth hormone receptor cDNA. Mol. Cell. Endocrinol. 99: 111–117, 1994.
 191. Moller, C., A. Hansson, B. Enberg, P. E. Lobie, and G. Norstedt. Growth hormone induction of tyrosine phosphorylation and activation of mitogen activated protein kinases in cells transfected with rat GH receptor cDNA. J. Biol. Chem. 267: 23403–23408, 1992.
 192. Morikawa, M., T. Nixon, and H. Green. Growth hormone and the adipose conversion of 3T3 cells. Cell 29: 783–789, 1982.
 193. Mosley, B., M. P. Beckmann, C. J. March, R. L. Idzerda, S. D. Gimpel, T. VandenBos, D. Friend, A. Alpert, D. Anderson, J. Jackson, J. M. Wignall, C. Smith, B. Gallis, J. E. Sims, D. Urdal, M. B. Widmer, D. Cosman, and L. S. Park. The murine interleukin‐4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell 59: 335–348, 1989.
 194. Mosley, B., C. De Imus, D. Friend, N. Boiani, B. Thoma, L. S. Park, and D. Cosman. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling sub‐unit conferring OSM‐specific receptor activation. J. Biol. Chem. 271: 32635–32643, 1996.
 195. Mui, A. L., H. Wakao, A. M. O'Farrell, N. Harada, and A. Miyajima. Interleukin‐3, granulocyte‐macrophage colony stimulating factor and interleukin‐5 transduce signals through two STAT5 homologs. EMBO J. 14: 1166–1175, 1995.
 196. Muller, M., J. Briscoe, C. Laxton, D. Guschin, A. Ziemiecki, O. Silvennoinen, A. G. Harpur, G. Barbieri, B. A. Witthuhn, and C. Schindler. The protein tyrosine kinase JAK1 complements defects in interferon‐alpha/beta and‐gamma signal transduction. Nature 366: 129–135, 1993.
 197. Mullis, P. E., T. Lund, M. S. Patel, C G D. Brook, and P. M. Brickell. Regulation of human growth hormone receptor gene expression by human growth hormone in a human hepatoma cell line. Mol. Cell. Endocrinol. 76: 125–133, 1991.
 198. Murakami, M., M. Narazaki, M. Hibi, H. Yawata, K. Yasukawa, M. Hamaguchi, T. Taga, and T. Kishimoto. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc. Natl. Acad. Sci. USA 88: 11349–11353, 1991.
 199. Murata, T., P. D. Noguchi, and R. K. Puri. IL‐13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL‐4 and IL‐13 signaling. J. Immunol. 156: 2972–2978, 1996.
 200. Murphy, L. J., G. I. Bell, and H. G. Friesen. Growth hormone stimulates sequential induction of c‐myc and insulin‐like growth factor I expression in vivo. Endocrinology 120: 1806–1812, 1987.
 201. Myers, M. G., Jr., X. J. Sun, B. Cheatham, B. R. Jachna, E. M. Glasheen, J. M. Backer, and M. F. White. IRS‐1 is a common element in insulin and insulin‐like growth factor‐1 signaling to the phosphatidylinositol 3′‐kinase. Endocrinology 132: 1421–1430, 1993.
 202. Myers, M. G., Jr., L.‐M. Wang, X. J. Sun, Y. Zhang, L. Yenush, J. Schlessinger, J. H. Pierce, and M. F. White. Role of IRS‐1‐GRB‐2 complexes in insulin signaling. Mol. Cell. Biol. 14: 3577–3587, 1994.
 203. Myers, M. G., Jr., and M. F. White. Insulin signal transduction and the IRS proteins. Annu. Rev. Pharmacol. Toxicol. 36: 615–658, 1996.
 204. Nagata, Y., and K. Todokoro. Interleukin 3 activates not only JAK2 and STAT5, but also Tyk2, STAT1, and STAT3. Biochem. Biophys. Res. Commun. 221: 785–789, 1996.
 205. Nakamura, N., H. Chin, N. Miyasaka, and O. Miura. An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells. J. Biol. Chem. 271: 19483–19488, 1996.
 206. Nebert, D. W. Proposed role of drug‐metabolizing enzymes: regulation of steady state levels of the ligands that effect growth, homeostasis, differentiation, and neuroendocrine functions. Mol. Endocrinol. 5: 1203–1214, 1991.
 207. Nebert, D. W., D. R. Nelson, M. J. Coon, R. W. Estabrook, R. Feyereisen, Y. Fujii‐Kuriyama, F. J. Gonzalez, F. P. Guengerich, I. C. Gunsalus, and E. F. Johnson. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature [erratum appears in DNA Cell. Biol. 10: 397–398, 1991]. DNA Cell. Biol. 10: 1–14, 1991.
 208. Nelson, S. A., and D. M. Robins. Two distinct mechanisms elicit androgen‐dependent expression of the mouse sex‐limited protein gene. Mol. Endocrinol. 11: 460–469, 1997.
 209. Nicholson, S. E., A. C. Oates, A. G. Harpur, A. Ziemiecki, A. F. Wilks, and J. E. Layton. Tyrosine kinase JAK1 is associated with the granulocyte‐colony stimulating factor receptor and both become tyrosine‐phosphorylated after receptor activation. Proc. Natl. Acad. Sci. USA 91: 2985–2988, 1994.
 210. Nilsson, A., B. Carlsson, L. Mathews, and OGP Isaksson. Growth hormone regulation of the growth hormone receptor mRNA in cultured rat epiphyseal chondrocytes. Mol. Cell. Endocrinol. 70: 237–246, 1990.
 211. Noguchi, T., T. Matozaki, K. Horita, Y. Fujioka, and M. Kasuga. Role of SH‐PTP2, a protein‐tyrosine phosphatase with Src homology 2 domains, in insulin‐stimulated Ras activation. Mol. Cell. Biol. 14: 6674–6682, 1994.
 212. Norstedt, G., A. Mode, P. Eneroth, and J. Gustafsson. Induction of prolactin receptors in rat liver after the administration of growth hormone. Endocrinology 108: 1855–1861, 1981.
 213. Novick, D., B. Cohen, and M. Rubinstein. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 77: 391–400, 1994.
 214. Obiri, N. I., W. Debinski, W. J. Leonard, and R. K. Puri. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J. Biol. Chem. 270: 8797–8804, 1995.
 215. Ohmichi, M., K. Matuoka, T. Takenawa, and A. R. Saltiel. Growth factors differentially stimulate the phosphorylation of Shc proteins and their association with Grb2 in PC‐12 pheochromocytoma cells. J. Biol. Chem. 269: 1143–1148, 1994.
 216. O'Neal, K. D., and L.‐Y. Yu‐Lee. The proline‐rich motif (PRM): a novel feature of the cytokine receptor superfamily. Lymphokine Cytokine Res. 12: 309–312, 1993.
 217. O'Neill, T. J., A. Craparo, and T. A. Gustafson. Characterization of an interaction between insulin receptor substrate 1 and the insulin receptor by using the two‐hybrid system. Mol. Cell. Biol. 14: 6433–6442, 1994.
 218. Paquereau, L., M.J. Vilarem, V. Rossi, J. F. Rouayrenc, and A. Le Cam. Regulation of two rat serine‐protease inhibitor gene promoters by somatotropin and glucocorticoids. Study with intact hepatocytes and cell‐free systems. Eur. J. Biochem. 209: 1053–1061, 1992.
 219. Parini, P., B. Angelin, P. E. Lobie, G. Norstedt, and M. Rudling. Growth hormone specifically stimulates the expression of low density lipoprotein receptors in human hepatoma cells. Endocrinology 136: 3767–3773, 1995.
 220. Patthy, L. Homology of a domain of the growth hormone/prolactin receptor family with type III modules of fibronectin. Cell 61: 13–14, 1990.
 221. Patti, M. E., X. J. Sun, J. C. Bruening, E. Araki, M. A. Lipes, M. F. White, and C. R. Kahn. 4PS/insulin receptor substrate (IRS)‐2 is the alternative substrate of the insulin receptor in IRS‐1‐deficient mice. J. Biol. Chem. 270: 24670–24673, 1995.
 222. Pawson, T., and J. Schlessinger. SH2 and SH3 domains. Curr. Biol. 3: 434–442, 1993.
 223. Pennica, D., K. J. Shaw, T. A. Swanson, M. W. Moore, D. L. Shelton, K. A. Zioncheck, A. Rosenthal, T. Taga, N. F. Paoni, and W. I. Wood. Cardiotrophin‐1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J. Biol. Chem. 270: 10915–10922, 1995.
 224. Peter, M. A., K. H. Winterhalter, M. A. Peter, M. Boni‐Schnetzler, E. R. Froesch, and J. Zapf. Regulation of insulin‐like growth factor‐I (IGF‐I) and IGF‐binding proteins by growth hormone in rat white adipose tissue. Endocrinology 133: 2624–2631, 1993.
 225. Polotskaya, A., Y. Zhao, M. B. Lilly, and A. S. Kraft. Mapping the intracytoplasmic regions of the alpha granulocyte‐macrophage colony‐stimulating factor receptor necessary for cell growth regulation. J. Biol. Chem. 269: 14607–14613, 1994.
 226. Pons, S., T. Asano, E. Glasheen, M. Miralpeix, Y. Zhang, T. L. Fisher, M. G. Myers, Jr., X. J. Sun, and M. F. White. The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3‐kinase. Mol. Cell. Biol. 15: 4453–4465, 1995.
 227. Potter, J. J., V. W. Yang, and E. Mezey. Regulation of the rat class I alcohol dehydrogenase gene by growth hormone. Biochem. Biophys. Res. Commun. 191: 1040–1045, 1993.
 228. Pradines‐Figueres, A., S. Barcellini‐Couget, C. Dani, C. Vannier, and G. Ailhaud. Transcriptional control of the expression of lipoprotein lipase gene by growth hormone in preadipoctye OB1771 cells. J. Lipid Res. 31: 1283–1291, 1990.
 229. Quelle, D. E., F. W. Quelle, and D. M. Wojchowski. Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization. Mol. Cell. Biol. 12: 4553–4561, 1992.
 230. Quelle, F. W., N. Sato, B. A. Witthuhn, R. C. Inhorn, M. Eder, A. Miyajima, J. D. Griffin, and J. N. Ihle. JAK2 associates with the beta c chain of the receptor for granulocyte‐macrophage colony‐stimulating factor, and its activation requires the membrane‐proximal region. Mol. Cell. Biol. 14: 4335–4341, 1994.
 231. Quelle, F. W., W. Thierfelder, B. A. Witthuhn, B. Tang, S. Cohen, and J. N. Ihle. Phosphorylation and activation of the DNA binding activity of purified Statl by the Janus protein‐tyrosine kinases and the epidermal growth factor receptor. J. Biol. Chem. 270: 20775–20780, 1995.
 232. Quelle, F. W., D. Wang, T. Nosaka, W. E. Thierfelder, D. Stravopodis, Y. Weinstein, and J. N. Ihle. Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Mol. Cell. Biol. 16: 1622–1631, 1996.
 233. Ram, P. A., S. H. Park, H. K. Choi, and D. J. Waxman. Growth hormone activation of Stat 1, Stat 3, and Stat 5 in rat liver. Differential kinetics of hormone desensitization and growth hormone stimulation of both tyrosine phosphorylation and serine/threonine phosphorylation. J. Biol. Chem. 271: 5929–5940, 1996.
 234. Rao, P., T. Kitamura, A. Miyajima, and R. A. Mufson. Human IL‐3 receptor signaling: rapid induction of phosphatidylcholine hydrolysis is independent of protein kinase C but dependent on tyrosine phosphorylation in transfected NIH 3T3 cells. J. Immunol. 154: 1664–1674, 1995.
 235. Rao, P., and R. A. Mufson. Human interleukin‐3 stimulates a phosphatidylcholine specific phospholipase C and protein kinase C translocation. Cancer Res. 54: 777–783, 1994.
 236. Raz, R., J. E. Durbin, and D. E. Levy. Acute phase response factor and additional members of the interferon‐stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. J. Biol. Chem. 269: 24391–24395, 1994.
 237. Ren, H. Y., N. Komatsu, R. Shimizu, K. Okada, and Y. Miura. Erythropoietin induces tyrosine phosphorylation and activation of phospholipase C‐gamma 1 in a human erythropoietin‐dependent cell line. J. Biol. Chem. 269: 19633–19638, 1994.
 238. Renauld, J. C., C. Druez, A. Kermouni, F. Houssiau, C. Uyttenhove, E. Van Roost, and J. Van Snick. Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc. Natl. Acad. Sci. USA 89: 5690–5694, 1992.
 239. Ridderstrale, M., E. Degerman, and H. Tornqvist. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate‐1 and its association with phosphatidylinositol 3‐kinase in primary adipocytes. J. Biol. Chem. 270: 3471–3474, 1995.
 240. Ridderstrale, M., and H. Tornqvist. PI‐3‐kinase inhibitor wort‐mannin blocks the insulin‐like effects of growth hormone in isolated rat adipocytes. Biochem. Biophys. Res. Commun. 203: 306–310, 1994.
 241. Ridderstrale, M., and H. Tornqvist. Effects of tyrosine kinase inhibitors on tyrosine phosphorylations and the insulin‐like effects in response to human growth hormone in isolated rat adipocytes. Endocrinology 137: 4650–4656, 1996.
 242. Ripperger, J. A., S. Fritz, K. Richter, G. M. Hocke, F. Lottspeich, and G. H. Fey. Transcription factors Stat3 and Stat5b are present in rat liver nuclei late in an acute phase response and bind interleukin‐6 response elements. J. Biol. Chem. 270: 29998–30006, 1995.
 243. Rivera, V. M., C. K. Miranti, R. P. Misra, D. D. Ginty, R.‐H. Chen, J. Blenis, and M. E. Greenberg. A growth factor‐induced kinase phosphorylates the serum response factor at a site that regulates its DNA‐binding activity. Mol. Cell. Biol. 13: 6260–6273, 1993.
 244. Robertson, J. A., L. A. Haldosen, T. J. Wood, M. K. Steed, and J. A. Gustafsson. Growth hormone pretranslationally regulates the sexually dimorphic expression of the prolactin receptor gene in rat liver. Mol. Endocrinol. 4: 1235–1239, 1990.
 245. Robertson, L. M., T. K. Kerppola, M. Vendrell, D. Luk, R. J. Smeyne, C. Bocchiaro, J. I. Morgan, and T. Curran. Regulation of c‐fos expression in transgenic mice requires multiple interdependent transcription control elements. Neuron 14: 241–252, 1995.
 246. Rodriguez‐Linares, B., and S. P. Watson. Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation. Biochem. J. 316: 93–98, 1996.
 247. Rogers, S. A., and M. R. Hammerman. Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney. Proc. Natl. Acad. Sci. USA 86: 6363–6366, 1989.
 248. Rolling, C., D. Treton, S. Pellegrini, P. Galanaud, and Y. Richard. IL4 and IL13 receptors share the gamma c chain and activate STAT6, STAT3 and STAT5 proteins in normal human B cells. FEBS Lett. 393: 53–56, 1996.
 249. Roy, A. K., B. Chatterjee, W. F. Demyan, B. S. Milin, N. M. Motwani, T. S. Nath, and M. J. Schiop. Hormone and age‐dependent regulation of alpha 2μ‐globulin gene expression. Recent Prog. Horm. Res. 39: 425–461, 1983.
 250. Rozakis‐Adcock, M., and P. A. Kelly. Identification of ligand binding determinants of the prolactin receptor. J. Biol. Chem. 267: 7428–7433, 1992.
 251. Rui, H., R. A. Kirken, and W. L. Farrar. Activation of receptor‐associated tyrosine kinase JAK2 by prolactin. J. Biol. Chem. 269: 5364–5368, 1994.
 252. Russell, S. M., J. A. Johnston, M. Noguchi, M. Kawamura, C. M. Bacon, M. Friedmann, M. Berg, D. W. McVicar, B. A. Witthuhn, O. Silvennoinen, A. S. Goldman, F. C. Schmalstieg, J. N. Ihle, J. J. O'Shea, and W. J. Leonard. Interaction of IL‐2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266: 1042–1045, 1994.
 253. Sands, W. A., V. Bulut, A. Severn, D. Xu, and F. Y. Liew. Inhibition of nitric oxide synthesis by interleukin‐4 may involve inhibiting the activation of protein kinase C epsilon. Eur. J. Immunol. 24: 2345–2350, 1994.
 254. Sato, S., T. Katagiri, Y. Kikuchi, Y. Hitoshi, S. Yonehara, S. Tsukada, D. Kitamura, T. Watanabe, and O. Witte. IL‐5 receptor‐mediated tyrosine phosphorylation of SH2/Sh3‐containing proteins and activation of Bruton's tyrosine and Janus 2 kinases. J. Exp. Med. 180: 2101–2111, 1994.
 255. Scharfmann, R., F. Atouf, A. Tazi, and P. Czernichow. Growth hormone and prolactin regulate the expression of nerve growth factor receptors in INS‐1 cells. Endocrinology 134: 2321–2328, 1994.
 256. Schmitt‐Ney, M., B. Happ, R. K. Ball, and B. Groner. Developmental and environmental regulation of a mammary gland‐specific nuclear factor essential for transcription of the gene encoding beta‐casein. Proc. Natl. Acad. Sci. USA 89: 3130–3134, 1992.
 257. Schwartz, J. Growth hormone directly alters glucose utilization in 3T3 adipocytes. Biochem. Biophys. Res. Commun. 125: 237–243, 1984.
 258. Schwartz, J., and C. Carter‐Su. Effects of growth hormone on glucose metabolism and glucose transport in 3T3–F442A cells. Dependence on cell differentiation. Endocrinology 122: 2247–2256, 1988.
 259. Schwartz, J., and S. Eden. Acute growth hormone deficiency rapidly alters glucose metabolism in rat adipocytes. Relation to insulin responses and binding. Endocrinology 116: 1806–1812, 1985.
 260. Schwartz, Y., and H. M. Goodman. Refractoriness to the insulin‐like effects of growth hormone depends upon calcium. Endocrinology 126: 170–176, 1990.
 261. Schwartz, Y., H. Yamaguchi, and H. M. Goodman. Growth hormone increases intracellular free calcium in rat adipocytes: correlation with actions on carbohydrate metabolism. Endocrinology 131: 772–778, 1992.
 262. Seeburg, P. H., J. Shine, J. A. Martial, J. D. Baxter, and H. M. Goodman. Nucleotide sequence and amplification in bacteria of structural gene for rat growth hormone. Nature 270: 486–494, 1977.
 263. Seger, R., and E. Krebs. The MAPK signaling cascade. FASEB J. 9: 726–735, 1995.
 264. Sekine, N., S. Ullrich, R. Regazzi, W. F. Pralong, and C. B. Wollheim. Postreceptor signalling of growth hormone and prolactin and their effects in the differentiated insulin‐secreting cell line, INS‐1. Endocrinology 137: 1841–1850, 1996.
 265. Seneviratne, C., J. Luo, and L. J. Murphy. Transcriptional regulation of rat insulin‐like growth factor‐binding protein‐1 expression by growth hormone. Mol. Endocrinol. 4: 1199–1204, 1990.
 266. Shimoda, K., H. Iwasaki, S. Okamura, Y. Ohno, A. Kubota, F. Arima, T. Otsuka, and Y. Niho. G‐CSF induces tyrosine phosphorylation of the JAK2 protein in the human myeloid G‐CSF responsive and proliferative cells, but not in mature neutrophils. Biochem. Biophys. Res. Commun. 203: 922–928, 1994.
 267. Shuai, K., C. Schindler, V. R. Prezioso, and J. E. Darnell, Jr. Activation of transcription by IFN‐gamma: tyrosine phosphorylation of a 91‐kD DNA binding protein. Science 258: 1808–1812, 1992.
 268. Shuai, K., G. R. Stark, I. M. Kerr, and J. E. Darnell, Jr. A single phosphotyrosine residue of Stat91 required for gene activation by interferon‐gamma. Science 261: 1744–1746, 1993.
 269. Silva, C. M., R. N. Day, M. J. Weber, and M. O. Thorner. Human growth hormone (GH) receptor is characterized as the 134‐kilodalton tyrosine‐phosphorylated protein activated by GH treatment in IM‐9 cells. Endocrinology 133: 2307–2312, 1993.
 270. Silva, C. M., H. Lu, and R. N. Day. Characterization and cloning of STAT5 from IM‐9 cells and its activation by growth hormone. Mol. Endocrinol. 10: 508–518, 1996.
 271. Silva, C. M., H. Lu, M. J. Weber, and M. O. Thorner. Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon‐gamma in IM‐9 cells. J. Biol. Chem. 269: 27532–27539, 1994.
 272. Silva, C. M., M. J. Weber, and M. O. Thorner. Stimulation of tyrosine phosphorylation in human cells by activation of the growth hormone receptor. Endocrinology 132: 101–108, 1993.
 273. Silvennoinen, O., J. N. Ihle, J. Schlessinger, and D. E. Levy. Interferon‐induced nuclear signalling by Jak protein tyrosine kinase. Nature 366: 583–585, 1993.
 274. Silvennoinen, O., B. Witthuhn, F. W. Quelle, J. L. Cleveland, T. Yi, and J. N. Ihle. Structure of the murine JAK2 protein‐tyrosine kinase and its role in interleukin 3 signal transduction. Proc. Natl. Acad. Sci. USA 90: 8429–8433, 1993.
 275. Silverman, M. S., D. C. Mynarcik, R. E. Corin, H. C. Haspel, and M. Sonenberg. Antagonism by growth hormone of insulin‐sensitive hexose transport in 3T3‐F442A adipocytes. Endocrinology 125: 2600–2604, 1989.
 276. Skolnik, E. Y., C. H. Lee, A. Batzer, L. M. Vicentini, M. Zhou, R. Daly, M. G. Myers, Jr., J. M. Backer, A. Ullrich, M. F. White, and J. Schlessinger. The SH2/SH3 domain‐containing protein Grb2 interacts with tyrosine‐phosphorylated IRS1 and Shc: implications for insulin control of ras signaling. EMBO J. 12: 1929–1936, 1993.
 277. Slootweg, M. C., R. P. de Groot, M. P. Herrmann‐Erlee, I. Koornneef, W. Kruijer, and Y. M. Kramer. Growth hormone induces expression of c‐jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c‐fos oncogene expression. J. Mol. Endocrinol. 6: 179–188, 1991.
 278. Slootweg, M. C., S. T. van Genesen, A. P. Otte, S. A. Duursma, and W. Kruijer. Activation of mouse osteoblast growth hormone receptor; c‐fos oncogene expression independent of phosphoinositide breakdown and cyclic AMP. J. Mol. Endocrinol. 4: 265–274, 1990.
 279. Smal, J., and P. De Meyts. Role of kinase C in the insulin‐like effects of human growth hormone in rat adipocytes. Biochem. Biophys. Res. Commun. 147: 1232–1240, 1987.
 280. Smit, L. S., D. J. Meyer, N. Billestrup, G. Norstedt, J. Schwartz, and C. Carter‐Su. The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. Mol. Endocrinol. 10: 519–533, 1996.
 281. Smit, L. S., J. A. VanderKuur, A. Stimage, Y. Han, G. Luo, L.‐Y. Yulee, J. Schwartz, and C. Carter‐Su. Growth hormone‐induced tyrosyl phosphorylation and DNA binding activity of Stat5A and Stat5B. Endocrinology 138: 3426–3434, 1997.
 282. Smith, W. C., J. Kuniyoshi, and F. Talamantes. Mouse serum growth hormone (GH) binding protein has GH receptor extracellular and substituted transmembrane domains. Mol. Endocrinol. 3: 984–990, 1989.
 283. Soh, J., R. J. Donnelly, S. Kotenko, T. M. Mariano, J. R. Cook, N. Wang, S. Emanuel, B. Schwartz, T. Miki, and S. Pestka. Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell 76: 793–802, 1994.
 284. Sotiropoulos, A., S. Moutoussamy, N. Binart, P. A. Kelly, and J. Finidori. The membrane proximal region of the cytoplasmic domain of the growth hormone receptor is involved in the activation of Stat 3. FEBS Lett. 369: 169–172, 1995.
 285. Sotiropoulos, A., S. Moutoussamy, F. Renaudie, M. Clauss, C. Kayser, F. Gouilleux, P. A. Kelly, and J. Finidori. Differential activation of Stat3 and Stat5 by distinct regions of the growth hormone receptor. Mol. Endocrinol. 10: 998–1009, 1996.
 286. Sotiropoulos, A., M. Perrot‐Applanat, H. Dinerstein, A. Pallier, M. C. Postel‐Vinay, J. Finidori, and P. A. Kelly. Distinct cytoplasmic regions of the growth hormone receptor are required for activation of JAK2, mitogen‐activated protein kinase, and transcription. Endocrinology 135: 1292–1298, 1994.
 287. Souza, S. C., G. P. Frick, R. Yip, R. B. Lobo, L.‐R. Tai, and H. M. Goodman. Growth hormone stimulates tyrosine phosphorylation of insulin receptor substrate‐1. J. Biol. Chem. 269: 30085–30088, 1994.
 288. Stahl, N., T. G. Boulton, T. Farruggella, N. Y. Ip, S. Davis, B. A. Witthuhn, F. W. Quelle, O. Silvennoinen, G. Barbieri, S. Pellegrini, J. N. Ihle, and G. D. Yancopoulos. Association and activation of Jak‐Tyk kinases by CNTF‐LIF‐OSM‐IL‐6 beta receptor components. Science 263: 92–95, 1994.
 289. Stahl, N., T. J. Farruggella, T. G. Boulton, Z. Zhong, J. E. Darnell, Jr., and G. D. Yancopoulos. Modular tyrosine‐based motifs in cytokine receptors specify choice of STATs and other substrates. Science 267: 1349–1353, 1995.
 290. Strous, G. J., P. van Kerkhof, R. Covers, A. Ciechanover, and A. L. Schwartz. The ubiquitin conjugation system is required for ligand‐induced endocytosis and degradation of the growth hormone receptor. EMBO J. 15: 3806–3812, 1996.
 291. Stubbart, J. R., D. F. Barton, P.‐K. K. Tai, S. E. Stred, E. Gorin, H. M. Goodman, and C. Carter‐Su. Antibodies to cytoplasmic sequences of cloned liver growth hormone (GH) receptors recognize GH receptors associated with tyrosine kinase activity. Endocrinology 129: 1659–1670, 1991.
 292. Subramanian, A., J. Teixeira, J. Wang, and G. Gil. A STAT factor mediates the sexually dimorphic regulation of hepatic cytochrome P450 3A10/lithocholic acid 6beta‐hydroxylase gene expression by growth hormone. Mol. Cell. Biol. 15: 4672–4682, 1995.
 293. Sumantran, V. N., M. L. Tsai, and J. Schwartz. Growth hormone induces c‐fos and c‐jun expression in cells with varying requirements for differentiation. Endocrinology 130: 2016–2024, 1992.
 294. Sun, X. J., D. L. Crimmins, M. G. Myers, Jr., M. Miralpeix, and M. F. White. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS‐1. Mol. Cell. Biol. 13: 7418–7428, 1993.
 295. Sun, X. J., S. Pons, T. Asano, M. G. Myers, Jr., E. Glasheen, and M. F. White. The Fyn tyrosine kinase binds Irs‐1 and forms a distinct signaling complex during insulin stimulation. J. Biol. Chem. 271: 10583–10587, 1996.
 296. Sun, X. J., P. Rothenberg, C. R. Kahn, J. M. Backer, E. Araki, P. A. Wilden, D. A. Cahill, B. J. Goldstein, and M. F. White. Structure of the insulin receptor substrate IRS‐1 defines a unique signal transduction protein. Nature 352: 73–77, 1991.
 297. Sun, X.‐J., L.‐M. Wang, Y. Zhang, L. Yenush, M. G. Myers, Jr., E. Giasheen, W. S. Lane, J. H. Pierce, and M. F. White. Role of IRS‐2 in insulin and cytokine signalling. Nature 377: 173–177, 1995.
 298. Sundseth, S. S., J. A. Alberta, and D. J. Waxman. Sex‐specific, growth hormone‐regulated transcription of the cytochrome P450 2C11 and 2C12 genes. J. Biol. Chem. 267: 3907–3914, 1992.
 299. Tagaya, Y., J. D. Burton, Y. Miyamoto, and T. A. Waldmann. Identification of a novel receptor/signal transduction pathway for IL‐15/T in mast cells. EMBO J. 15: 4928–4939, 1996.
 300. Tai, P.‐K. K., J.‐F. Liao, E. H. Chen, J. J. Dietz, J. Schwartz, and C. Carter‐Su. Differential regulation of two glucose transporters by chronic growth hormone treatment of cultured 3T3‐F442A adipose cells. J. Biol. Chem. 265: 21828–21834, 1990.
 301. Takaki, S., A. Tominaga, Y. Hitoshi, E. Sonoda, N. Yamaguchi, and K. Takatsu. Molecular cloning and expression of the murine interleukin‐5 receptor. EMBO J. 9: 4367–4374, 1990.
 302. Takaya, K., Y. Ogawa, N. Isse, T. Okazaki, N. Satoh, H. Masuzaki, K. Mori, N. Tamura, K. Hosoda, and K. Nakao. Molecular cloning of rat leptin receptor isoform complementary DNAs—identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem. Biophys. Res. Commun. 225: 75–83, 1996.
 303. Takeshita, T., H. Asao, K. Ohtani, N. Ishii, S. Kumaki, N. Tanaka, H. Munakata, M. Nakamura, and K. Sugamura. Cloning of the gamma chain of the human IL‐2 receptor. Science 257: 379–382, 1992.
 304. Tanaka, N., H. Asao, K. Ohbo, N. Ishii, T. Takeshita, M. Nakamura, H. Sasaki, and K. Sugamura. Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor beta and gamma chains. Proc. Natl. Acad. Sci. USA 91: 7271–7275, 1994:
 305. Tannenbaum, G. S., and J. B. Martin. Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology 98: 562–570, 1976.
 306. Tanner, J. W., W. Chen, R. L. Young, G. D. Longmore, and A. S. Shaw. The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. J. Biol. Chem. 270: 6523–6530, 1995.
 307. Tartaglia, L. A., M. Dembski, X. Weng, N. Deng, J. Culpepper, R. Devos, G. J. Richards, L. A. Campfield, F. T. Clark, and J. Deeds. Identification and expression cloning of a leptin receptor, OB‐R. Cell 83: 1263–1271, 1995.
 308. Thomas, M. J., K. Kikuchi, D. P. Bichell, and P. Rotwein. Rapid activation of rat insulin‐like growth factor‐I gene transcription by growth hormone reveals no alterations in deoxyribonucleic acid‐protein interactions within the major promoter. Endocrinology 135: 1584–1592, 1994.
 309. Thomas, M. J., K. Kikuchi, D. P. Bichell, and P. Rotwein. Characterization of deoxyribonucleic acid‐protein interactions at a growth hormone‐inducible nuclease hypersensitive site in the rat insulin‐like growth factor‐I gene. Endocrinology 136: 562–569, 1995.
 310. Toker, A., M. Meyer, K. K. Reddy, J. R. Falck, R. Aneja, S. Aneja, A. Parra, D. J. Burns, L. M. Ballas, and L. C. Cantley. Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns‐3,4‐P2 and PtdIns‐3,4,5‐P3. J. Biol. Chem. 269: 32358–32367, 1994.
 311. Toilet, P., B. Enberg, and A. Mode. Growth hormone (GH) reglation of cytochrome P‐450IIC12, insulin‐like growth factor‐1 (IGF‐1), and GH receptor messenger RNA expression in primary rat hepatocytes: a hormonal interplay with insulin, IGF‐1, and thyroid hormone. Mol. Endocrinol. 4: 1934–1942, 1990.
 312. Toilet, P., M. Hamberg, J.‐A. Gustafsson, and A. Mode. Growth hormone signaling leading to CYP2C12 gene expression in rat hepatocytes involves phospholipase A2. J. Biol. Chem. 270: 12569–12577, 1995.
 313. Toilet, P., C. Legraverend, J.‐A. Gustafsson, and A. Mode. A role for protein kinases in the growth hormone regulation of cytochrome P4502C12 and insulin‐like growth factor‐I messenger RNA expression in primary adult rat hepatocytes. Mol. Endocrinol. 5: 1351–1358, 1991.
 314. Tourkine, N., C. Schindler, M. Larose, and L. M. Houdebine. Activation of STAT factors by prolactin, interferon‐gamma, growth hormone, and a tyrosine phosphatase inhibitor in rabbit primary mammary epithelial cells. J. Biol. Chem. 270: 20952–20961, 1995.
 315. Treisman, R. The serum response element. Trends Biochem. Sci. 17: 423–426, 1992.
 316. Uddin, S., L. Yenush, X. J. Sun, M. E. Sweet, M. F. White, and L. C. Plantanias. Interferon‐alpha engages the insulin receptor substrate‐1 to associate with the phosphatidylinositol 3′‐kinase. J. Biol. Chem. 270: 15938–15941, 1995.
 317. Uze, G., G. Lutfalla, and I. Gresser. Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell 60: 225–234, 1990.
 318. VanderKuur, J., G. Allevato, N. Billestrup, G. Norstedt, and C. Carter‐Su. Growth hormone‐promoted tyrosyl phosphorylation of Shc proteins and Shc association with Grb2. J. Biol. Chem. 270: 7587–7593, 1995.
 319. VanderKuur, J. A., E. R. Butch, S. B. Waters, J. E. Pessin, K.‐L. Guan, and C. Carter‐Su. Signalling molecules involved in coupling growth hormone receptor to MAP kinase activation. Endocrinology 138: 4301–4307, 1997.
 320. VanderKuur, J., X. Wang, L. Zhang, G. Allevato, N. Billestrup, and C. Carter‐Su. Growth hormone‐dependent phosphorylation of tyrosine 333 and/or 338 of the growth hormone receptor. J. Biol. Chem. 270: 21738–21744, 1995.
 321. VanderKuur, J. A., X. Wang, L. Zhang, G. S. Campbell, G. Allevato, N. Billestrup, G. Norstedt, and C. Carter‐Su. Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase. J. Biol. Chem. 269: 21709–21717, 1994.
 322. Vigon, I., J.‐P. Mornon, L. Cocault, M.‐T. Mitjavila, P. Tambourin, S. Gisselbrecht, and M. Souyri. Molecular cloning and characterization of MPL, the human homolog of the v‐mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc. Natl. Acad. Sci. USA 89: 5640–5644, 1992.
 323. Vikman, K., B. Carlsson, H. Billig, and S. Eden. Expression and regulation of growth hormone (GH) receptor messenger ribonucleic acid (mRNA) in rat adipose tissue, adipocytes, and adipocyte precursor cells: GH regulation of GH receptor mRNA. Endocrinology 129: 1155–1161, 1991.
 324. Vinson, C. R., P. B. Sigler, and S. L. McKnight. Scissorsgrip model for DNA recognition by a family of leucine zipper proteins. Science 246: 911–916, 1989.
 325. Wakao, H., F. Gouilleux, and B. Groner. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response [erratum appears in EMBO J. 14: 854–855, 1995]. EMBO J. 13: 2182–2191, 1994.
 326. Wang, L.‐M., A. D. Keegan, W. Li, G. E. Lienhard, S. Pacini, J. S. Gutkind, M. G. Myers, Jr., X.‐J. Sun, M. F. White, S. A. Aaronson, W. E. Paul, and J. H. Pierce. Common elements in interleukin 4 and insulin signaling pathways in factor‐dependent hematopoietic cells. Proc. Natl. Acad. Sci. USA 90: 4032–4036, 1993.
 327. Wang, L.‐M., M. G. Myers, Jr., X.‐J. Sun, S. A. Aaronson, M. F. White, and J. H. Pierce. IRS‐1: essential for insulin‐and IL‐4‐stimulated mitogenesis in hematopoietic cells. Science 261: 1591–1594, 1993.
 328. Wang, X., C. J. Darus, B. C. Xu, and J. J. Kopchick. Identification of growth hormone receptor (GHR) tyrosine residues required for GHR phosphorylation and JAK2 and STAT5 activation. Mol. Endocrinol. 10: 1249–1260, 1996.
 329. Wang, X., M. D. Uhler, N. Billestrup, G. Norstedt, F. Talamantes, J. H. Nielsen, and C. Carter‐Su. Evidence for association of the cloned liver growth hormone receptor with a tyrosine kinase. J. Biol. Chem. 267: 17390–17396, 1992.
 330. Wang, Y., K. K. Morella, J. Ripperger, C. F. Lai, D. P. Gearing, G. H. Fey, S. P. Campos, and H. Baumann. Receptors for interleukin‐3 (IL‐3) and growth hormone mediate an IL‐6‐type transcriptional induction in the presence of JAK2 or STAT3. Blood 86: 1671–1679, 1995.
 331. Wang, Y.‐D., K. Wong, and W. I. Wood. Intracellular tyrosine residues of the human growth hormone receptor are not required for the signaling of proliferation or Jak‐STAT activation. J. Biol. Chem. 270: 7021–7024, 1995.
 332. Wang, Y.‐D., and W. I. Wood. Amino acids of the human growth hormone receptor that are required for proliferation and Jak‐STAT signaling. Mol. Endocrinol. 9: 303–311, 1995.
 333. Wartmann, M., N. Cella, P. Hofer, B. Groner, X. Liu, L. Hennighausen, and N. E. Hynes. Lactogenic hormone activation of Stat5 and transcription of the beta‐casein gene in mammary epithelial cells is independent of p42 ERK2 mitogen‐activated protein kinase activity. J. Biol. Chem. 271: 31863–31868, 1996.
 334. Watanabe, S., T. Itoh, and K. Arai. JAK2 is essential for activation of c‐fos and c‐myc promoters and cell proliferation through the human granulocyte‐macrophage colony‐stimulating factor receptor in BA/F3 cells. J. Biol. Chem. 271: 12681–12686, 1996.
 335. Waters, S. B., K. Yamauchi, and J. E. Pessin. Insulin‐stimulated disassociation of the SOS‐Grb2 complex. Mol. Cell. Biol. 15: 2791–2799, 1995.
 336. Watling, D., D. Guschin, M. Müller, O. Silvennoinen, B. A. Witthuhn, F. W. Quelle, N. C. Rogers, C. Schindler, G. R. Stark, J. N. Ihle, and I. M. Kerr. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon‐gamma signal transduction pathway. Nature 366: 166–170, 1993.
 337. Watowich, S. S., A. Yoshimura, G. D. Longmore, D. J. Hilton, Y. Yoshimura, and H. F. Lodish. Homodimerization and constitutive activation of the erythropoietin receptor. Proc. Natl. Acad. Sci. USA 89: 2140–2144, 1992.
 338. Waxman, D. J., P. A. Ram, S. H. Park, and H. K. Choi. Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver‐expressed, Stat 5‐related DNA binding protein. Proposed role as an intracellular regulator of male‐specific liver gene transcription. J. Biol. Chem. 270: 13262–13270, 1995.
 339. Waxman, D. J., S. Zhao, and H. K. Choi. Interaction of a novel sex‐dependent, growth hormone‐regulated liver nuclear factor with CYP2C12 promotor. J. Biol. Chem. 271: 29978–29987, 1996.
 340. Wegenka, U. M., C. Lutticken, J. Buschmann, J. Yuan, F. Lottspeich, W. Muller‐Esterl, C. Schindler, E. Roeb, P. C. Heinrich, and F. Horn. The interleukin‐6‐activated acute‐phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol. Cell. Biol. 14: 3186–3196, 1994.
 341. Welham, M. J., L. Learmonth, H. Bone, and J. W. Scharader. Interleukin‐13 signal transduction in lymphohemopoietic cells. J. Biol. Chem. 270: 12286–12296, 1995.
 342. Wells, J. A., B. C. Cunningham, G. Fuh, H. B. Lowman, S. H. Bass, M. G. Mulkerrin, M. Ultsch, and A. M. DeVos. The molecular basis for growth hormone‐receptor interactions. Recent Prog. Horm. Res. 48: 253–275, 1993.
 343. Wen, Z., Z. Zhong, and J. E. Darnell, Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82: 241–250, 1995.
 344. Whitmarsh, A. J., P. Shore, A. D. Sharrocks, and R. J. Davis. Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403–407, 1995.
 345. Wilks, A. F., A. G. Harpur, R. R. Kurban, S. J. Ralph, G. Zurcher, and A. Ziemiecki. Two novel protein‐tyrosine kinases, each with a second phosphotransferase‐related catalytic domain, define a new class of protein kinase. Mol. Cell. Biol. 11: 2057–2065, 1991.
 346. Winer, L. M., M. A. Shaw, and G. Baumann. Basal plasma growth hormone levels in man: new evidence for rhythmicity of growth hormone secretion. J. Clin. Endocrinol. Metab. 70: 1678–1686, 1990.
 347. Winston, L. A., and P. J. Berrics. Growth hormone stimulates the tyrosyl phosphorylation of 42‐ and 45‐kDa ERK‐related proteins. J. Biol. Chem. 267: 4747–4751, 1992.
 348. Winston, L. A., and T. Hunter. JAK2, Ras, and Raf are required for activation of extracellular signal‐regulated kinase/mitogen‐activated protein kinase by growth hormone. J. Biol. Chem. 270: 30837–30840, 1995.
 349. Witthuhn, B. A., F. W. Quelle, O. Silvennoinen, T. Yi, B. Tang, O. Miura, and J. N. Ihle. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74: 227–236, 1993.
 350. Witthuhn, B. A., O. Silvennoinen, O. Miura, K. S. Lai, C. Cwik, E. T. Liu, and J. N. Ihle. Involvement of the Jak‐3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370: 153–157, 1994.
 351. Wood, T. J., D. Sliva, P. E. Lobie, T. J. Pircher, F. Gouilleux, H. Wakao, J. A. Gustafsson, B. Groner, G. Norstedt, and L. A. Haldosen. Mediation of growth hormone‐dependent transcriptional activation by mammary gland factor/Stat 5. J. Biol. Chem. 270: 9448–9453, 1995.
 352. Xu, B. C., X. Wang, C. J. Darus, and J. J. Kopchick. Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J. Biol. Chem. 271: 19768–19773, 1996.
 353. Yamasaki, K., T. Taga, Y. Hirata, H. Yawata, Y. Kawanishi, B. Seed, T. Taniguchi, T. Hirano, and T. Kishimoto. Cloning and expression of the human interleukin‐6 (BSF‐2/IFN beta 2) receptor. Science 241: 825–828, 1988.
 354. Yamauchi, K., and J. E. Pessin. Enhancement or inhibition of insulin signaling by insulin receptor substrate 1 is cell context dependent. Mol. Cell. Biol. 14: 4427–4434, 1994.
 355. Yi, W., S. O. Kim, J. Jiang, S. H. Park, A. S. Kraft, D. J. Waxman, and S. J. Frank. Growth hormone receptor cytoplasmic domain differentially promotes tyrosine phosphorylation of signal transducers and activators of transcription 5b and 3 by activated JAK2 kinase. Mol. Endocrinol. 10: 1425–1443, 1996.
 356. Yin, T., S. R. Kellers, F. W. Quelle, B. A. Witthuhn, M. L.‐S. Tsang, G. E. Lienhard, J. N. Ihle, and Y.‐C. Yang. Interleukin‐9 induces tyrosine phosphorylation of insulin receptor substrate‐1 via JAK tyrosine kinases. J. Biol. Chem. 270: 20497–20502, 1995.
 357. Yin, T., K. Yasukawa, T. Taga, T. Kishimoto, and Y.‐C. Yang. Identification of a 130‐kilodalton tyrosine‐phosphorylated protein induced by interleukin‐11 as JAK2 tyrosine kinase, which associates with gp130 signal transducer. Exp. Hematol. 22: 467–472, 1994.
 358. Yoon, J. B., S. A. Berry, S. Seelig, and H. C. Towle. An inducible nuclear factor binds to a growth hormone‐regulated gene. J. Biol. Chem. 265: 19947–19954, 1990.
 359. Yoon, J. B., H. C. Towle, and S. Seeling. Growth hormone induces two mRNA species of the serine protease inhibitor gene family in rat liver. J. Biol. Chem. 262: 4284–4289, 1987.
 360. Zeng, Y. X., H. Takahashi, M. Shibata, and K. Hirokawa. JAK3 Janus kinase is involved in interleukin 7 signal pathway. FEBS Lett. 353: 289–293, 1994.
 361. Zhang, X., J. Blenis, H.‐C. Li, C. Schindler, and S. Chen‐Kiang. Requirement of serine phosphorylation for formation of STAT‐promoter complexes. Science 267: 1990–1994, 1995.
 362. Zhong, Z., Z. Wen, and J. E. Darnell, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin‐6. Science 264: 95–98, 1994.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Lisa S. Smit, Debra J. Meyer, Lawrence S. Argetsinger, Jessica Schwartz, Christin Carter‐Su. Molecular Events in Growth Hormone–Receptor Interaction and Signaling. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 445-480. First published in print 1999. doi: 10.1002/cphy.cp070514