Comprehensive Physiology Wiley Online Library

Protein Kinases and Phosphatases in Cellular Signaling

Full Article on Wiley Online Library


The sections in this article are:

1 Protein Kinase and Phosphatase Classification
2 Protein Kinase Structure
2.1 Serine/Threonine Kinases
2.2 Tyrosine Kinases
2.3 Dual‐Specificity Kinases
3 Protein Phosphatase Structure
3.1 Serine/Threonine Phosphatases
3.2 Tyrosine Phosphatases
3.3 Dual‐Specificity Phosphatases
4 Kinase and Phosphatase Regulation
4.1 Localization
4.2 Phosphorylation
4.3 Regulation via Autoinhibitory Domains
4.4 Substrate Specificity
5 Protein Kinase C
5.1 Structure
5.2 Isozyme Specificity
5.3 Isozymes in Cellular Function
6 Calcineurin
6.1 Enzyme Structure
6.2 Isoforms
6.3 Substrate Specificity
6.4 Endogenous Substrates
6.5 T‐Cell Activation
6.6 Nuclear Factor of Activated T Cells as a Substrate
6.7 FK506 and Cyclosporin A as Probes of Calcineurin Action
7 Role of CDC25 in Cell‐Cycle Progression
7.1 Overview of Cell‐Cycle Proteins
7.2 Cdc2
7.3 Cdc25
8 Conclusions
Figure 1. Figure 1.

Structure of protein kinase C (PKC) enzymes. Conserved (C1–4) regions are indicated. C1 contains two cysteine‐rich regions and binds phorbol ester/diacyglycerol (DAG). Atypical PKCs contain only one cysteine‐rich region and do not bind DAG/phorbol ester. C2 is responsible for calcium‐binding activity, and the ATP‐binding site is in C3.

Figure 2. Figure 2.

Schematic of calcineurin A‐subunit, showing the catalytic domain, (CaN B)—binding domain, calmodulin (CaM)‐binding domain, and autoinhibitory domain (AID)

Figure 3. Figure 3.

Schematic of T‐cell calcineurin (CaN) activation pathway. Antigen stimulation of the T‐cell receptor (TCR) results in increased cytosolic calcium levels, resulting in CaN activation. CaN dephosphorylates (either directly or indirectly) the nuclear factor of activated T cells (NFAT). Dephosphorylated NFAT translocates to the nucleus, where it regulates induction of several cytokine genes, including interleukin 2 and tumor necrosis factor‐α.

Figure 4. Figure 4.

Schematic of cdc2 kinase regulation. Cyclin B binds to cdc2, which is phosphorylated on Thr14, Tyr15 (by wee1), and Thr161 (by cdk‐activating kinase [CAK]). The cdc25 phosphatase induces mitosis by dephosphorylating Thr14 and Tyr15. Exit from mitosis is regulated by cyclin degradation and Thr161 dephosphorylation.

Figure 1.

Structure of protein kinase C (PKC) enzymes. Conserved (C1–4) regions are indicated. C1 contains two cysteine‐rich regions and binds phorbol ester/diacyglycerol (DAG). Atypical PKCs contain only one cysteine‐rich region and do not bind DAG/phorbol ester. C2 is responsible for calcium‐binding activity, and the ATP‐binding site is in C3.

Figure 2.

Schematic of calcineurin A‐subunit, showing the catalytic domain, (CaN B)—binding domain, calmodulin (CaM)‐binding domain, and autoinhibitory domain (AID)

Figure 3.

Schematic of T‐cell calcineurin (CaN) activation pathway. Antigen stimulation of the T‐cell receptor (TCR) results in increased cytosolic calcium levels, resulting in CaN activation. CaN dephosphorylates (either directly or indirectly) the nuclear factor of activated T cells (NFAT). Dephosphorylated NFAT translocates to the nucleus, where it regulates induction of several cytokine genes, including interleukin 2 and tumor necrosis factor‐α.

Figure 4.

Schematic of cdc2 kinase regulation. Cyclin B binds to cdc2, which is phosphorylated on Thr14, Tyr15 (by wee1), and Thr161 (by cdk‐activating kinase [CAK]). The cdc25 phosphatase induces mitosis by dephosphorylating Thr14 and Tyr15. Exit from mitosis is regulated by cyclin degradation and Thr161 dephosphorylation.

 1. Aaronson, S. A. Growth factors and cancer. Science 254: 1146–1150, 1991.
 2. Aderem, A. Signal transduction and the actin cytoskeleton: the roles of MARCKS and profilin. Trends. Biol. Sci. 17: 438–443, 1992.
 3. Aderem, A. The MARCKS brothers: a family of protein kinase C substrates. Cell 71: 713–716, 1992.
 4. Ahmad, S., and R. I. Glazer. Expression of the antisense cDNA for protein kinase Cα attenuates resistance in doxorubicin‐resistant MCF‐7 breast carcinoma cells. Mol. Pharmacol. 43: 858–862, 1993.
 5. Ahmed, S., I. N. Maruyama, R. Kozma, J. Lee, S. Brenner, and L. Lim. The Caenorhabditis elegans unc‐13 gene product is a phospholipid‐dependent high‐affinity phorbol ester receptor. Biochem. J. 287: 995–999, 1992.
 6. Ahmad, S., T. Mineta, R. L. Martuza, and R. I. Glazer. Antisense expression of protein kinase Cα inhibits the growth and tumori‐genicity of human glioblastoma cells. Neurosurgery 35: 904–909, 1994.
 7. Ahn, N. G. The MAP kinase cascade. Discovery of a new signal transduction pathway. Mol. Cell. Biochem. 127: 201–209, 1993.
 8. Aitken, A., P. Cohen, S. Santikarn, D. H. Williams, A. G. Calder, A. Smith, and C. B. Klee. Identification of the NH2‐terminal blocking group of calcineurin B as myristic acid. FEBS Lett. 150: 314–318, 1982.
 9. Aitken, A., C. B. Klee, and P. Cohen. The structure of subunit B of calcineurin. Eur. J. Biochem. 139: 663–671, 1984.
 10. Akimoto, K., K. Mizuno, S. Osada, S. Hirai, S. Tanuma, K. Suzuki, and S. Ohno. A new member of the third class in the protein kinase C family, PKC lambda, expressed dominantly in an undifferentiated mouse embryonal carcinoma cell line and also in many tissues and cells. J. Biol. Chem. 269: 12677–12683, 1994.
 11. Akita, Y., S. Ohno, Y. Yajima, and K. Suzuki. Possible role of Ca2+‐independent protein kinase C isozyme, nPKC, in thyrotropin‐releasing hormone‐stimulated signal transduction: differential downregulation in GH4C1 cells. Biochem. Biophys. Res. Commun. 172: 184–189, 1990.
 12. Anthony, F. A., D. L. Merat, and W. Y. Cheung. A spectrofluorimetric assay of calmodulin‐dependent protein phosphatase using 4‐methylumbelliferyl phosphate. Anal. Biochem. 155: 103–108, 1986.
 13. Antoni, F. A., M. J. Shipston, and S. M. Smith. Inhibitory role for calcineurin in stimulus‐secretion coupling revealed by FK506 and cyclosporin A in pituitary corticotrope tumor cells. Biochem. Biophys. Res. Commun. 194: 226–233, 1993.
 14. Areces, L. B., M. G. Kazanietz, and P. M. Blumberg. Close similarity of baculovirus‐expressed n‐chimaerin and protein kinase Cα as phorbol ester receptors. J. Biol. Chem. 269: 19553–19558, 1994.
 15. Asaoka, Y., M. Oka, K. Yoshida, Y. Sasaki, and Y. Nishizuka. Role of lysophosphatidylcholine in T‐lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C. Proc. Natl. Acad. Sci. U.S.A. 1992.
 16. Augert, G., P. F. Blackmore, and J. H. Exton. Changes in the concentration and fatty acid composition of phosphoinositides induced by hormones in hepatocytes. J. Biol. Chem. 264: 2574–2580, 1989.
 17. Azzi, A., D. Boscoboinik, and C. Hensey. The protein kinase C family. Eur. J. Biochem. 208: 547–557, 1992.
 18. Baier, G., D. Telford, L. Giampa, K. M. Coggeshall, G. Baier‐Bitterlick, N. Isakov, and A. Altman. Molecular cloning and characterization of PKC, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. J. Biol. Chem. 268: 4997–5004, 1993.
 19. Bierer, B. E., P. S. Mattila, R. F. Standaert, L. A. Herzenberg, S. J. Burakoff, G. Crabtree, and S. L. Schreiber. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc. Natl. Acad. Sci. U.S.A. 87: 9231–9235, 1990.
 20. Bierer, B. E., P. K. Somers, T. J. Wandless, S. J. Burakoff, and S. L. Schreiber. Probing immunosuppressant action with a nonnatural immunophilin ligand. Science 250: 556–558, 1990.
 21. Blumenthal, D. K., K. Takio, R. S. Hansen, and E. G. Krebs. Dephosphorylation of cAMP‐dependent protein kinase regulatory subunit (type II) by calmodulin‐dependent protein phosphatase. J. Biol. Chem. 261: 8140–8145, 1986.
 22. Bocckino, S. B., P. F. Blackmore, and J. H. Exton. Stimulation of 1,2‐diacylglycerol accumulation in hepatocytes by vasopressin, epinephrine, and angiotensin II. J. Biol. Chem. 260: 14201–14207, 1985.
 23. Bonnefoy‐Berard, N., L. Genestier, M. Flacher, and J. P. Revillard. The phosphoprotein phosphatase calcineurin controls calcium‐dependent apoptosis in B cell lines. Eur. J. Immunol. 24: 325–329, 1994.
 24. Castagna, M., Y. Takai, K. Kaibuchi, K. Sano, U. Kikkawa, and Y. Nishizuka. Direct activation of calcium‐activated, phospholipid‐dependent protein kinase by tumor‐promoting phorbol esters. J. Biol. Chem. 257: 7847–7851, 1982.
 25. Chang, C. D., H. Mukai, T. Kuno, and C. Tanaka. cDNA cloning of an alternatively spliced isoform of the regulatory subunit of Ca2+/calmodulin‐dependent protein phosphatase (calcineurin Bα2). Biochim. Biophys. Acta 1217: 174–180, 1994.
 26. Chang, J. D., Y. Xu, M. K. Raychowdhury, and J. A. Ware. Molecular cloning and expression of a cDNA encoding a novel isoenzyme of protein kinase C (nPKC). J. Biol. Chem. 268: 14208–14214, 1993.
 27. Chapline, C., K. Ramsay, T. Klauck, and S. Jaken. Interaction cloning of protein kinase C substrates. J. Biol. Chem. 268: 6858–6861, 1993.
 28. Charbonneau, H., and N. K. Tonks. 1002 protein phosphatases? Annu. Rev. Cell Biol. 8: 463–493, 1992.
 29. Charbonneau, H., N. K. Tonks, K. A. Walsh, and E. H. Fischer. The leukocyte common antigen (CD45): a putative receptor‐linked protein tyrosine phosphatase. Proc. Natl. Acad. Sci. U.S.A. 85: 7182–7186, 1988.
 30. Charollais, R. H., S. Tiwari, and N.S.B. Thomas. Into and out of G1: the control of cell proliferation. Biochimie 76: 887–894, 1994.
 31. Chida, K., N. Kato, and T. Kuroki. Down regulation of phorbol diester receptors by proteolytic degradation of protein kinase C in a cultured cell line of fetal rat skin keratinocytes. J. Biol. Chem. 261: 13013–13018, 1986.
 32. Clarke, P. R. Switching off MAP kinases. Curr. Biol. 4: 647–650, 1994.
 33. Clarke, P. R., D. Leiss, M. Pagano, and E. Karsenti. Cyclin A‐and cylin B‐dependent kinases are regulated by different mechanisms in Xenopus egg extracts. EMBO J. 11: 1751–1761, 1992.
 34. Clipstone, N. A., and G. R. Crabtree. Identification of calcineurin as a key signalling enzyme in T‐lymphocyte activation. Nature 357: 695–697, 1992.
 35. Clipstone, N. A., D. F. Fiorentino, and G. R. Crabtree. Molecular analysis of the interaction of calcineurin with drug‐immunophilin complexes. J. Biol. Chem. 269: 26431–26437, 1994.
 36. Coghlan, V. M., B. A. Perrino, M. Howard, L. K. Langeberg, J. B. Hicks, W. M. Gallatin, and J. D. Scott. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267: 108–112, 1995.
 37. Cohen, P. Signal integration at the level of protein kinases, protein phosphatases and their substrates. Trends Biol. Sci. 17: 408–413, 1992.
 38. Cohen, P., and P.T.W. Cohen. Protein phosphatases come of age. J. Biol. Chem. 264: 21435–21438, 1989.
 39. Coleman, T. R., and W. G. Dunphy. Cdc2 regulatory factors. Curr. Biol. 6: 877–882, 1994.
 40. Coleman, T. R., Z. Tang, and W. G. Dunphy. Negative regulation of the Wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer. Cell 72: 919–929, 1993.
 41. Conklin, D. S., K. Galaktionov, and D. Beach. 14–3–3 proteins associate with cdc25 phosphatases. Proc. Natl. Acad. Sci. U.S.A. 92: 7892–7896, 1995.
 42. Crabtree, G. R., and N. A. Clipstone. Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu. Rev. Biochem. 63: 1045–1083, 1993.
 43. Dean, N. M., and R. McKay. Inhibition of protein kinase C‐α expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc. Natl. Acad. Sci. U.S.A. 91: 11762–11766, 1994.
 44. Dean, N. M., R. McKay, T. P. Condon, and C. F. Bennett. Inhibition of protein kinase C‐α expression in human A549 cells by antisense oligonucleotides inhibits induction of intracellular adhesion molecule 1 (ICAM‐1) mRNA by phorbol esters. J. Biol. Chem. 269: 16416–16424, 1994.
 45. DeBondt, H. L., J. Rosenblatt, J. Jancarik, H. D. Jones, D. O. Morgan, and S. Kim. Crystal structure of cyclin‐dependent kinase 2. Nature 363: 595–602, 1993.
 46. Dekker, L. V., and P. J. Parker. Protein kinase C‐–a question of specificity. Trends Biol. Sci. 19: 73–77, 1994.
 47. Denu, J. M., and J. E. Dixon. A catalytic mechanism for the dual‐specific phosphatases. Proc. Natl. Acad. Sci. U.S.A. 92: 5910–5914, 1995.
 48. Denu, J. M., G. Zhou, L. Wu, R. Zhao, J. Yuvaniyama, M. A. Saper, and J. E. Dixon. The purification and characterization of a human dual‐specific protein tyrosine phosphatase. J. Biol. Chem. 270: 3796–3803, 1995.
 49. Desai, D., H. C. Wessling, R. P. Fisher, and D. O. Morgan. Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2. Mol. Cell. Biol. 15: 345–350, 1995.
 50. Desdoutis, F., J. C. Siciliano, P. Greengard, and J. Girault. Dopamine‐ and cAMP‐regulated phosphoprotein DARPP‐32: phosphorylation of ser‐137 by casein kinase I inhibits dephosphorylation of thr‐34 by calcineurin. Proc. Natl. Acad. Sci. U.S.A. 92: 2682–2685, 1995.
 51. Diaz‐Meco, M. T., E. Berra, M. A. Munico, L. Sanz, J. Lozano, I. Dominguez, V. Diaz‐Golpe, M. T. Lain de Lera, J. Alcami, C. V. Paya, F. Arenzana‐Seisdedos, J. Virelizier, and J. Moscat. A dominant negative protein kinase C zeta subspecies blocks NF‐kB activation. Mol. Cell. Biol. 13: 4770–4775, 1993.
 52. Divecha, N., H. Banfic, and R. F. Irvine. The phosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF‐1) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus. EMBO J. 10: 3207–3214, 1991.
 53. Donella‐Dean, A., M. H. Krinks, M. Ruzzene, C. B. Klee, and L. A. Pinna. Dephosphorylation of phosphopeptides by calcineurin (protein phosphatase 2B). Eur. J. Biochem. 219: 109–117, 1994.
 54. Draetta, G. Cell cycle control in eukaryotes: molecular mechanisms of cdc2 activation. Trends. Biol. Sci. 15: 379–383, 1990.
 55. Dulic, V., W. K. Kaufmann, S. J. Wilson, T. D. Tisty, E. Lees, J. W. Harper, S. J. Elledge, and S. I. Reed. p53‐dependent inhibition of cyclin‐dependent kinase activities in human fibroblasts during radiation‐induced G1 arrest. Cell 76: 1013–1023, 1994.
 56. Dumont, F. J., M. J. Staruch, S. K. Koprak, M. R. Melino, and N. H. Sigal. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK506 and rapamycin. J. Immunol. 144: 251–258, 1990.
 57. Dunphy, W. G., and A. Kumagai. The cdc25 protein contains an intrinsic phosphatase activity. Cell 67: 189–196, 1991.
 58. Dutz, J. P., D. A. Fruman, S. J. Burakoff, and B. E. Bierer. A role for calcineurin in degranulation of murine cytotoxic T lymphocytes. J. Immunol. 150: 2591–2598, 1993.
 59. El‐Deiry, W. S., J. W. Harper, P. M. O'Connor, V. E. Velculescu, C. E. Canman, J. Jackman, J. A. Pietenpol, M. Burrell, D. E. Hill, Y. Wang, K. G. Wiman, W. E. Mercer, M. B. Kastan, K. W. Kohn, S. J. Elledge, K. W. Kinzler, and B. Vogelstein. WAF1/CIP1 is induced in p53‐mediated G1 arrest and apoptosis. Cancer Res. 54: 1169–1174, 1994.
 60. Emmel, E. A., C. L. Verweij, D. B. Durand, K. M. Higgins, E. Lacy, and G. R. Crabtree. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 246: 1617–1619, 1989.
 61. Enoch, T., and P. Nurse. Mutation of fission yeast cell cycle control genes abolishes dependence of mitosis on DNA replication. Cell 60: 665–673, 1990.
 62. Exton, J. H. Signaling through phosphatidylcholine breakdown. J. Biol. Chem. 265: 1–4, 1990.
 63. Farrar, W. L., T. P. Thomas, and W. B. Anderson Altered cytosol/membrane enzyme redistribution on interleukin‐3 activation of protein kinase C. Nature 315: 235–237, 1985.
 64. Feaver, W., J. Q. Svejstrup, N. L. Henry, and R. D. Kornberg. Relationship of cdk‐activating kinase and RNA polymerase II CTD kinase TFIIH/TFIIK. Cell 79: 1103–1109, 1994.
 65. Fernandez, A., J. Mery, M. Vandromme, M. Basset, J. Cavadore, and N.J.C. Lamb. Effective intracellular inhibition of the cAMP‐dependent protein kinase by microinjection of a modified form of the specific inhibitor peptide PKI in living fibroblasts. Exp. Cell Res. 195: 468–477, 1991.
 66. Ferreira, A., R. L. Kincaid, and K. S. Kosik. Calcineurin is associated with the cytoskeleton of cultured neurons and has a role in the acquisition of polarity. Mol. Biol. Cell 4: 1225–1238, 1993.
 67. Fields, A. P., S. M. Pincus, A. S. Kraft, and W. S. May. Interleukin‐3 and bryostatin 1 mediate rapid nuclear envelope protein phosphorylation in growth factor‐dependent FDC‐P1 hematopoietic cells. A possible role for nuclear protein kinase C. J. Biol. Chem. 264: 21896–21901, 1989.
 68. Fields, A. P., G. Tyler, A. S. Kraft, and W. S. May. Role of nuclear protein kinase C in the mitogenic response to platelet‐derived growth factor. J. Cell Sci. 96: 107–114, 1990.
 69. Firpo, E. J., A. Koff, M. J. Solomon, and J. M. Roberts. Inactivation of a cdk2 inhibitor during interleukin 2‐induced proliferation of human T lymphocytes. Mol. Cell. Biol. 14: 4889–4901, 1994.
 70. Fischer, E. H. Protein phosphorylation: a historical overview. In: Signal Transduction and Protein Phosphorylation, edited by L.M.G. Heilmeyer New York: Plenum Press, 1987, p. 3–10.
 71. Fischer, E. H., H. Charbonneau, and N. K. Tonks. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science 253: 401–406, 1991.
 72. Flanagan, W. M., B. Corthesy, R. J. Bram, and G. R. Crabtree. Nuclear association of a T‐cell transcription factor blocked by FK‐506 and cyclosporin A. Nature 352: 803–807, 1991.
 73. Fruman, D. A., C. B. Klee, B. E. Bierer, and B. E. Burakoff. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK506 and cyclosporin A. Proc. Natl. Acad. Sci. U.S.A. 89: 3686–3690, 1992.
 74. Fruman, D. A., P. E. Mather, S. J. Burakoff, and B. E. Bierer. Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas. Eur. J. Immunol. 22: 2513–2517, 1992.
 75. Fu, H., K. Xia, D. C. Pallas, C. Cui, K. Conroy, R. P. Narsimhan, H. Mamon, R. J. Collier, and T. M. Roberts. Interaction of the protein kinase Raf‐1 with 14–3–3 proteins. Science 266: 126–129, 1994.
 76. Galaktionov, K., and D. Beach. Specific activation of cdc25 tyrosine phosphatases by B‐type cyclins: evidence for multiple roles of mitotic cyclins. Cell 67: 1181–1194, 1991.
 77. Galaktionov, K., C. Jessus, and D. Beach. Raf1 interaction with cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. Genes Dev. 9: 1046–1058, 1995.
 78. Galaktionov, K., A. K. Lee, J. Eckstein, G. Draetta, J. Meckler, M. Loda, and D. Beach. cdc25 phosphatases as potential human oncogenes. Science 269: 1575–1578, 1995.
 79. Gautier, J., M. J. Solomon, R. N. Booher, J. F. Bazan, and M. W. Kirschner. cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell 67: 197–211, 1991.
 80. Genot, E. M., P. J. Parker, and D. A. Cantrell. Analysis of the role of protein kinase C‐α, ‐, and ‐zeta in T cell activation. J. Biol. Chem. 270: 9833–9839, 1995.
 81. Gerard, F., U. Strausfeld, A. Fernandez, and N. J. Lamb. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: 1169–1172, 1991.
 82. Girard, F., U. Strausfield, J. Cavadore, P. Russell, A. Fernandez, and N.J.C. Lamb. cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells. J. Cell. Biol. 118: 785–794, 1992.
 83. Giri, P. R., S. Higuchi, and R. L. Kincaid. Chromosomal mapping of the human genes for the calmodulin‐dependent protein phosphatase (calcineurin) catalytic subunit. Biochem. Biophys. Res. Commun. 181: 252–258, 1991.
 84. Giri, P. R., C. A. Marietta, S. Higuchi, and R. L. Kincaid. Molecular and phylogenetic analysis of calmodulin‐dependent protein phosphatase (calcineurin) catalytic subunit genes. DNA Cell Biol. 11: 415–424, 1992.
 85. Glotzer, M., A. W. Murray, and M. W. Kirschner. Cyclin is degraded by the ubiquitin pathway. Nature 349: 132–136, 1991.
 86. Go, M., K. Sekiguchi, H. Nomura, U. Kikkawa, and Y. Nishizuka. Further studies on the specificity of diacylglycerol for protein kinase C activation. Biochem. Biophys. Res. Commun. 144: 598–605, 1987.
 87. Godson, C., K. S. Bell, and P. A. Insel. Inhibition of expression of protein kinase C α by antisense cDNA inhibits phorbol estermediated arachidonate release. J. Biol. Chem. 268: 11946–11950, 1993.
 88. Goldberg, J., H. Huang, Y. Kwon, P. Greengard, A. C. Nairn, and J. Kuriyan. Three‐dimensional structure of the catalytic subunit of protein serine/threonine phosphatase‐1. Nature 376: 745–752, 1995.
 89. Gong, C. X., T. J. Singh, I. Grundke‐Iqbal, and K. Iqbal. Alzheimer's disease abnormally phosphorylated is dephosphorylated by protein phosphatase 2B (calcineurin). J. Neurochem. 62: 803–806, 1994.
 90. Goode, N., K. Hughes, J. R. Woodgett, and P. J. Parker. Differential regulation of glycogen synthase kinase‐3β by protein kinase C isotypes. J. Biol. Chem. 267: 16878–16882, 1992.
 91. Goodnight, J., H. Mischak, W. Kolch, and J. F. Mushinski. Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 cells. J. Biol. Chem. 270: 9991–10001, 1995.
 92. Gould, K. L., and P. Nurse. Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342: 39–45, 1989.
 93. Griffith, J. P., J. L. Kim, E. E. Kim, M. D. Sintchak, J. A. Thomson, M. J. Fitzgibbon, M. A. Fleming, P. R. Caron, K. Hsiao, and M. A. Navia. X‐ray structure of calcineurin inhibited by the immunophilin‐immunosuppressant FKBP12‐FK506 complex. Cell 82: 507–522, 1995.
 94. Groblewski, G. E., A. C. C. Wagner, and J. A. Williams. Cyclosporin A inhibits Ca2+/calmodulin‐dependent protein phosphatase and secretion in pancreatic acinar cells. J. Biol. Chem. 269: 15111–15117, 1994.
 95. Grove, J. R., P. J. Deutsch, D. J. Price, J. F. Habener, and J. Avruch. Plasmids encoding PKI (1–31), a specific inhibitor of cAMP‐stimulated gene expression, inhibit the basal transcriptional activity of some but not all cAMP‐regulated DNA response elements in JEG‐3 cells. J. Biol. Chem. 19506–19513, 1989.
 96. Grove, J. R., D. J. Price, H. M. Goodman, and J. Avruch. Recombinant fragment of protein kinase inhibitor blocks cyclic AMP‐dependent gene transcription. Science 238: 530–533, 1987.
 97. Guan, K., S. S. Broyles, and J. E. Dixon. A tyr/ser protein phosphatase encoded by vaccinia virus. Nature 350: 359–361, 1991.
 98. Guerini, D., M. J. Hubbard, M. H. Krinks, and C. B. Klee. Multiple forms of calcineurin, a brain isozyme of the calmodulin‐stimulated protein phosphatase. In: The Biology and Medicine of Signal Transduction, edited by Y. Nishizuka New York: Raven, 1990, p. 242–250.
 99. Guerini, D., and C. B. Klee. Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain. Proc. Natl. Acad. Sci. U.S.A. 86: 9183–9187, 1989.
 100. Guerini, D., M. H. Krinks, J. M. Sikela, W. E. Hahn, and C. B. Klee. Isolation and sequence of a cDNA clone for human calcineurin B, the calcium‐binding subunit of the calcium/calmodulin stimulated protein phosphatase. DNA 8: 675–682, 1989.
 101. Haddy, A., S. K. Swanson, T. L. Born, and F. Rusnak. Inhibition of calcineurin by cyclosporin A‐cyclophilin requires calcineurin B. FEBS Lett. 314: 37–40, 1992.
 102. Hagiwara, M., C. Uchida, N. Usuda, T. Nagata, and H. Kidaka. Zeta‐related protein kinase C in nuclei of nerve cells. Biochem. Biophys. Res. Commun. 168: 161–168, 1990.
 103. Haldar, S., N. Jena, and C. M. Croce. Inactivation of bcl‐2 by phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 92: 4507–4511, 1995.
 104. Hanks, S. K., and A. M. Quinn. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 200: 38–77, 1991.
 105. Hanks, S. K., A. M. Quinn, and T. Hunter. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241: 42–52, 1988.
 106. Hannon, G. J., and D. Beach. p15INK4B is a potential effector of TGF‐β‐induced cell cycle arrest. Nature 371: 257–260, 1994.
 107. Hardie, G. Pseudosubstrates turn off protein kinases. Nature 335: 592–593, 1988.
 108. Hartwell, L. H. and M. B. Kastan. Cell cycle control and cancer. Science 266: 1821–1828, 1994.
 109. Hashimoto, Y., B. A. Perrino, and T. R. Soderling. Identification of an autoinhibitory domain in calcineurin. J. Biol. Chem. 265: 1924–1927, 1990.
 110. Hathaway, D. R., R. S. Adelstein, and C. B. Klee. Interaction of calmodulin with myosin light chain kinase and cAMP‐dependent protein kinase in bovine brain. J. Biol. Chem. 256: 8183–8189, 1981.
 111. Hemmings, H. C., S. I. Walaas, C. C. Ouimet, and P. Greengard. Dopaminergic regulation of protein phosphorylation in the striatum: DARPP‐32. Trends Neurosci. 10: 377–383, 1987.
 112. Hendley, B., C. B. Klee, and F. R. Maxfield. Inhibition of neutrophil chemokinesis on vitronectin by inhibitors of calcineurin. Science 258: 296–299, 1992.
 113. Hershko, A., D. Ganoth, V. Sudakin, A. Dahan, L. H. Cohen, F. C. Luca, J. V. Ruderman, and E. Eytan. Components of a system that ligates cyclin to ubiquitin and their regulation by the protein kinase cdc2. J. Biol. Chem. 269: 4940–4946, 1994.
 114. Higuchi, S., J. Tamura, P. R. Giri, J. W. Polli, and R. L. Kincaid. Calmodulin‐dependent protein phosphatase from Neurospora crassa. J. Biol. Chem. 266: 18104–18112, 1991.
 115. Hirama, T., and H. P. Koeffler. Role of the cyclin‐dependent kinase inhibitors in the development of cancer. Blood 86: 841–854, 1995.
 116. Ho, S. N., D. J. Thomas, L. A. Timmerman, X. Li, U. Francke, and G. R. Crabtree. NFATc3, a lymphoid‐specific NFATc family member that is calcium‐regulated and exhibits distinct DNA binding specificity. J. Biol. Chem. 270: 19898–19907, 1995.
 117. Hocevar, B. A., D. J. Burns, and A. P. Fields. Identification of protein kinase C (PKC) phosphorylation sites on human lamin B. J. Biol. Chem. 268: 7545–7552, 1993.
 118. Hocevar, B. A., and A. P. Fields. Selective translocation of βII‐protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells. J. Biol. Chem. 266: 28–33, 1991.
 119. Hoffmann, I., P. R. Clarke, M. J. Marcote, E. Karsenti, and G. Draetta. Phosphorylation and activation of human cdc25‐C by cdc2‐cyclin B and its involvement in the self‐amplification of MPF at mitosis. EMBO J. 12: 53–63, 1993.
 120. Hoffmann, I., G. Draetta, and E. Karsenti. Activation of the phosphatase activity of human cdc25A by a cdk2‐cyclin E dependent phosphorylation at the G1/S transition. EMBO J. 13: 4302–4310, 1994.
 121. Hoffmann, I., and E. Karsenti. The role of cdc25 in checkpoints and feedback controls in the eukaryotic cell cycle. J. Cell Sci. 18: 75–79, 1994.
 122. Hommel, U., M. Zurini, and M. Luyten. Solution structure of a cysteine rich domain of rat protein kinase C. Nature Struct. Biol. 1: 383–387, 1994.
 123. Honda, R., Y. Ohba, A. Nagata, H. Okayama, and H. Yasuda. Dephosphorylation of human p34cdc2 kinase on both Thr‐14 and Tyr‐15 by human cdc25B phosphatase. FEBS Lett. 318: 331–334, 1993.
 124. Hoshi, M., T. Akiyama, Y. Shinohara, Y. Mitata, H. Ogawara, E. Nishida, and H. Sakai. Protein kinase C‐catalyzed phosphorylation of the microtubule‐binding domain of microtubule‐associated protein 2 inhibits its ability to induce tubulin polymerization. Eur. J. Biochem. 174: 225–230, 1988.
 125. Hsieh, J., P. W. Jurutka, M. A. Galligan, C. M. Terpening, C. A. Haussler, D. S. Samuels, Y. Shimizu, N. Shimizu, and M. R. Haussler. Human vitamin D receptor is selectively phosphorylated by protein kinase C on serine 51, a residue crucial to its trans‐activation function. Proc. Natl. Acad. Sci. U.S.A. 88: 9315–9319, 1991.
 126. Hubbard, M. J., and C. B. Klee. Functional domain structure of calcineurin A: mapping by limited proteolysis. Biochemistry 28: 1868–1874, 1989.
 127. Hunter, T. A thousand and one protein kinases. Cell 50: 823–829, 1987.
 128. Hunter, T. Protein kinase classification. Methods Enzymol. 200: 3–37, 1991.
 129. Hunter, T. Braking the cycle. Cell 75: 839–841, 1993.
 130. Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80: 225–236, 1995.
 131. Hunter, T., and J. Pines. Cyclins and cancer. Cell 66: 1071–1074, 1991.
 132. Hunter, T., and J. Pines. Cyclins and cancer II: cyclin D and cdk inhibitors come of age. Cell 79: 573–582, 1994.
 133. Husi, H., M. A. Luyten, and M. G. M. Zurini. Mapping of the immunophilin‐immunosuppressant site of interaction on calcineurin. J. Biol. Chem. 269: 14199–14204, 1994.
 134. Hyatt, S. L., L. Liao, C. Chapline, and S. Jaken. Identification and characterization of α‐protein kinase C binding proteins in normal and transformed REF52 cells. Biochemistry 33: 1223–1228, 1994.
 135. Ido, M., K. Sekiguchi, U. Kikkawa, and Y. Nishizuka. Phosphorylation of the EGF receptor from A431 epidermoid carcinoma cells by three distinct types of protein kinase C. FEBS Lett. 219: 215–218, 1987.
 136. Igarishi, M., A. Nagata, S. Jinno, K. Suto, and H. Okayama. Wee1+‐like gene in human cells. Nature 353: 80–82, 1991.
 137. Ikuta, T., K. Chida, O. Tajima, Y. Matsuura, M. Iwamori, Y. Ueda, K. Mizuno, S. Ohno, and T. Kuroki. Cholesterol sulfate, a novel activator for the eta isoform of protein kinase C. Cell Growth Differ. 5: 943–947, 1994.
 138. Irving, H. R., and J. H. Exton. Phosphatidylcholine breakdown in rat liver plasma membranes. Roles of guanine nucleotides and P2‐purigenic agonists. J. Biol. Chem. 262: 3440–3443, 1987.
 139. Ito, A., T. Hashimoto, M. Hirai, T. Takeda, H. Shuntoh, T. Kuno, and C. Tanaka. The complete primary structure of calcineurin A, a calmodulin binding protein homologous with protein phosphatases 1 and 2A. Biochem. Biophys. Res. Commun. 163: 1492–1497, 1989.
 140. Izumi, T., and J. L. Maller. Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M‐phase. Mol. Biol. Cell 4: 1337–1350, 1993.
 141. Izumi, T., and J. L. Maller. Phosphorylation and activation of the Xenopus cdc25 phosphatase in the absence of cdc2 and cdk2 kinase activity. Mol. Biol. Cell 6: 215–226, 1995.
 142. Izumi, T., D. M. Walker, and J. L. Maller. Periodic changes in phosphorylation of the Xenopus cdc25 phosphatase regulate its activity. Mol. Biol. Cell 3: 927–939, 1992.
 143. Jain, J., P. G. McCaffrey, Z. Miner, T. K. Kerppola, J. N. Lambert, G. L. Verdine, T. Curran, and A. Rao. The T‐cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 365: 352–355, 1993.
 144. Jain, J., P. G. McCaffrey, V. E. Valge‐Archer, and A. Rao. Nuclear factor of activated T cells contains Fos and Jun. Nature 356: 801–804, 1992.
 145. Jain, J., Z. Miner, and A. Rao. Analysis of the preexisting and nuclear forms of nuclear factor of activated T cells. J. Immunol. 151: 837–848, 1993.
 146. James, G., and E. N. Olson. Deletion of the regulatory domain of protein kinase C α exposes regions in the hinge and catalytic domains that mediate nuclear targeting. J. Cell Biol. 116: 863–874, 1992.
 147. Jarpe, M. B., K. L. Leach, and D. M. Raben. α‐Thrombin‐induced nuclear sn‐1,2‐diacylglycerols are derived from phosphatidylcholine hydrolysis in cultured fibroblasts. Biochemistry 33: 526–534, 1994.
 148. Jeffrey, P. D., A. A. Russo, K. Polyak, E. Gibbs, J. Hurwitz, J. Massague, and N. P. Pavletich. Mechanism of CDK activation revealed by the structure of a cyclin A‐CDK2 complex. Nature 376: 313–320, 1995.
 149. Jessus, C., and D. Beach. Oscillation of MPF is accompanied by periodic association between cdc25 and cdc2‐cyclin B. Cell 68: 323–332, 1992.
 150. Jia, Z., D. Barford, A. J. Flint, and N. K. Tonks. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268: 1754–1758, 1995.
 151. Jinno, S., K. Suto, A. Nagata, M. Igarashi, Y. Kanaoka, H. Nojima, and H. Okayama. Cdc25A is a novel phosphatase functioning early in the cell cycle. EMBO J. 13: 1549–1556, 1994.
 152. Kawamura, A., and M. S. Su. Interaction of FKBP12‐FK506 with calcineurin A at the B subunit‐binding site. J. Biol. Chem. 270: 15463–15466, 1995.
 153. Kazanietz, M. G., L. B. Areces, A. Bahador, H. Mischak, J. Goodnight, J. F. Mushinski, and P. M. Blumberg. Characterization of ligand and substrate specificity for the calcium‐dependent and calcium‐independent protein kinase C isozymes. Mol. Pharmacol. 44: 298–307, 1993.
 154. Kazanietz, M. G., X. R. Bustelo, M. Barbacid, W. Kolch, H. Mischak, G. Wong, G. R. Pettit, J. D. Bruns, and P. M. Blumberg. Zinc finger domains and phorbol ester pharmacophore. J. Biol. Chem. 269: 11590–11594, 1994.
 155. Kazanietz, M. G., S. Wang, G. W. A. Milne, N. E. Lewin, H. L. Liu, and P. M. Blumberg. Residues in the second cysteinerich region of protein kinase C δ relevant to phorbol ester binding as revealed by site‐directed mutagenesis. J. Biol. Chem. 270: 21852–21859, 1995.
 156. Kemp, B. E., and R. B. Pearson. Intrasteric regulation of protein kinases and phosphatases. Biochim. Biophys. Acta 1094: 67–76, 1991.
 157. Kemp, B. E., R. B. Pearson, C. House, P. J. Robinson, and A. R. Means. Regulation of protein kinases by pseudosubstrate prototopes. Cell. Signal. 1: 303–311, 1989.
 158. Kennelly, P. J., and E. G. Krebs. Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J. Biol. Chem. 266: 15555–15558, 1991.
 159. Keyomarsi, K., N. O'Leary, G. Molnar, E. Lees, H. J. Finger, and A. B. Pardee. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res. 380–385, 1994.
 160. Keyomarsi, K., and A. B. Pardee. Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc. Natl. Acad. Sci. U.S.A. 90: 1112–1116, 1993.
 161. Kiley, S. C., and S. Jaken. Protein kinase C: interactions and consequences. Trends Cell Biol. 4: 223–227, 1994.
 162. Kiley, S. C., P. J. Parker, D. Fabbro, and S. Jaken. Differential regulation of protein kinase C isozymes by thyrotropin‐releasing hormone in GH4C1 cells. J. Biol. Chem. 266: 23761–23768, 1991.
 163. Kiley, S. C., P. J. Parker, D. Fabbro, and S. Jaken. Hormone‐ and phorbol ester‐activated protein kinase C isozymes mediate a reorganization of the actin cytoskeleton associated with prolactin secretion in GH4C1 cells. Mol. Endocrinol. 6: 120–131, 1992.
 164. Kiley, S. C., D. Schaap, P. J. Parker, L.‐L. Hsie, and S. Jaken. Protein kinase C heterogeneity in GH4C1 rat pituitary cells. Characterization of a calcium‐independent phorbol ester receptor. J. Biol. Chem. 265: 15704–15712, 1990.
 165. Kincaid, R. L., C. D. Balaban, and M. L. Billingsley. Differential localization of calmodulin‐dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. Proc. Natl. Acad. Sci. U.S.A. 84: 1118–1122, 1987.
 166. Kincaid, R. L., P. R. Giri, S. Higuchi, J. Tamura, S. C. Dixon, C. A. Marietta, D. A. Amorese, and B. M. Martin. Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods. J. Biol. Chem. 265: 11312–11319, 1990.
 167. Kincaid, R. L., M. S. Nightingale, and B. M. Martin. Characterization of a cDNA clone encoding the calmodulin‐binding domain of mouse brain calcineurin. Proc. Natl. Acad. Sci. U.S.A. 85: 8983–8987, 1988.
 168. King, M. M., C. Y. Huang, P. B. Chock, A. C. Nairn, H. C. Hemmings, K. J. Chan, and P. Greengard. Mammalian brain phosphoproteins as substrates for calcineurin. J. Biol. Chem. 259: 8080–8083, 1984.
 169. Klee, C. B., and P. Cohen. The calmodulin‐regulated protein phosphatase. Mol. Aspects Cell Regul. 5: 225–248, 1988.
 170. Klee, C. B., T. H. Crouch, and M. H. Krinks. Calcineurin: a calcium and calmodulin‐binding protein of the nervous system. Proc. Natl. Acad. Sci. U.S.A. 76: 6270–6273, 1979.
 171. Klee, C. B., G. F. Draetta, and M. J. Hubbard. Calcineurin. Adv. Enzymol. Relat. Areas Mol. Biol. 61: 149–200, 1988.
 172. Klee, C. B., and M. H. Krinks. Purification of cyclic 3′,5′‐nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to sepharose. Biochemistry 17: 120–128, 1978.
 173. Klee, C. B., M. H. Krinks, A. J. Manalan, G. F. Draetta, and D. L. Newton. In: Advances in Protein Phosphatases 1, edited by W. Merlevede and J. DiSalvo. Belgium: Leuven University Press, 1985, p. 135–146.
 174. Klee, C. B., and T. C. Vanaman. Calmodulin. Adv. Prot. Chem. 35: 213–321, 1982.
 175. Kornbluth, S., B. Sebastian, T. Hunter, and J. Newport. Membrane localization of the kinase which phosphorylates p34cdc2 on threonine 14. Mol. Biol. Cell 5: 273–282, 1994.
 176. Kraft, A. S., and W. B. Anderson. Phorbol esters increase the amount of Ca2+, phospholipid‐dependent protein kinase associated with plasma membrane. Nature 301: 621–623, 1983.
 177. Krebs, E. G. The growth of research on protein phosphorylation. Trends Biochem. Sci. 19: 439, 1994.
 178. Krek, W., and E. A. Nigg. Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites. EMBO J. 10: 305–316, 1991.
 179. Kumagai, A., and W. G. Dunphy. The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell‐free system. Cell 64: 903–914, 1991.
 180. Kumagai, A., and W. G. Dunphy. Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. Cell 70: 139–151, 1992.
 181. Kunz, J., and M. N. Hall. Cyclosporin A, FK506 and rapamycin: more than just immunosuppression. Trends Biochem. Sci. 18: 334–338, 1993.
 182. Lea, J. P., J. M. Sands, S. J. McMahon, and J. A. Tumlin. Evidence that the inhibition of Na+/K+‐ATPase activity by FK506 involves calcineurin. Kidney Int. 46: 647–652, 1994.
 183. Leach, K. L., and P. M. Blumberg. Modulation of protein kinase C activity and [3H]phorbol 12,13‐dibutyrate binding by various tumor promoters in mouse brain cytosol. Cancer Res. 45: 1958–1963, 1985.
 184. Leach, K. L., E. A. Powers, V. A. Ruff, S. Jaken, and S. Kaufmann. Type 3 protein kinase C localization to the nuclear envelope of phorbol ester‐treated NIH 3T3 cells. J. Cell Biol. 109: 685–695, 1989.
 185. Leach, K. L., V. A. Ruff, M. B. Jarpe, L. D. Adams, D. Fabbro, and D. M. Raben. α‐Thrombin stimulates nuclear diglyceride levels and differential nuclear localization of protein kinase C isozymes in IIC9 cells. J. Biol. Chem. 267: 21816–21822, 1992.
 186. Leach, K. L., V. A. Ruff, T. M. Wright, M. S. Pessin, and D. M. Raben. Dissociation of protein kinase C activation and sn‐1,2‐diacylglycerol formation. J. Biol. Chem. 266: 3215–3221, 1991.
 187. Lee, M. S., T. Enoch, and H. Piwnica‐Worms. mik1+ encodes a tyrosine kinase that phosphorylates p34cdc2 on tyrosine 15. J. Biol. Chem. 269: 30530–30537, 1994.
 188. Lehel, C., Z. Olah, G. Jakab, and W. B. Anderson. Protein kinase C is localized to the Golgi via its zinc‐finger domain and modulates Golgi function. Proc. Natl. Acad. Sci. U.S.A. 92: 1406–1410, 1995.
 189. Levedakou, E. N., M. He, E. W. Baptist, R. J. Craven, W. G. Cance, P. L. Welcsh, A. Simmons, S. L. Naylor, R. J. Leach, T. B. Lewis, A. Bowcock, and E. T. Liu. Two novel human serine/threonine kinase with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern. Oncogene 9: 1977–1988, 1994.
 190. Lewin, B. Driving the cell cycle: M phase kinase, its partners, and substrates. Cell 64: 748–752, 1990.
 191. Li, H.‐C. Activation of brain calcineurin phosphatase towards nonprotein phosphoesters by Ca2+, calmodulin, and Mg2+. J. Biol. Chem. 265: 8801–8807, 1984.
 192. Li, X., S. N. Ho, J. Luna, J. Giacalone, D. J. Thomas, L. A. Timmerman, G. R. Crabtree, and U. Francke. Cloning and chromosomal localization of the human and murine genes for the T‐cell transcription factors NFATc and NFATp. Cytogenet. Cell Genet. 68: 185–191, 1995.
 193. Liao, L., S. L. Hyatt, C. Chapline, and S. Jaken. Protein kinase C domains involved in interactions with other proteins. Biochemistry 33: 1229–1233, 1994.
 194. Lindberg, R. A., M. A. Quinn, and T. Hunter. Dual‐specificity protein kinases: will any hydroxyl do? Trends Biochem. Sci. 17: 114–119, 1992.
 195. Liu, F., J. J. Stanton, Z. Wu, and H. Piwnica‐Worms. The human myt1 kinase preferentially phosphorylates cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Mol. Cell Biol. 17: 571–583, 1997.
 196. Liu, J. FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol. Today 14: 290–295, 1993.
 197. Liu, J., M. W. Albers, T. J. Wandless, S. Luan, D. G. Alberg, P. J. Belshaw, P. Cohen, C. MacKintosh, C. B. Klee, and S. L. Schreiber. Inhibition of T cell signaling by immunophilin‐ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry 31: 3896–3901, 1992.
 198. Liu, J., J. D. Farmer, W. S. Lane, J. Friedman, I. Weissman, and S. L. Schreiber. Calcineurin is a common target of cyclophilin‐cyclosporin A and FKBP‐FK506 complexes. Cell 66: 807–815, 1991.
 199. Liu, Y., and D. R. Storm. Dephosphorylation of neuromodulin by calcineurin. J. Biol. Chem. 264: 12800–12804, 1989.
 200. Lozano, J., E. Berra, M. M. Munico, M. T. Diaz‐Meco, I. Dominguez, L. Sanz, and J. Moscat. Protein kinase C zeta isoform is critical for kappa B‐dependent promoter activation by sphingomyelinase. J. Biol. Chem. 269: 19200–19202, 1994.
 201. Maier, J.A.M., and G. Ragnotti. An oligomer targeted against protein kinase Cα prevents interleukin‐1α induction of cyclooxygenase expression in human endothelial cells. Exp. Cell Res. 205: 52–58, 1993.
 202. Makela, T. P., J. Tassan, E. A. Nigg, S. Frutiger, G. J. Hughes, and R. A. Weinberg. A cyclin associated with the CDK‐activating kinase MO15. Nature 371: 254–257, 1994.
 203. Manalan, A. S., and C. B. Klee. Activation of calcineurin by limited proteolysis. Proc. Natl. Acad. Sci. U.S.A. 80: 4291–4295, 1983.
 204. Marais, R. M., O. Nguyen, J. R. Woodgett, and P. J. Parker. Studies on the primary sequence requirements for PKC‐α, ‐β1 and ‐γ peptide substrates. FEBS Lett. 277: 151–155, 1990.
 205. Marais, R. M., and P. J. Parker. Purification and characterization of bovine brain protein kinase C isotypes α, β and gamma. Eur. J. Biochem. 182: 129–137, 1989.
 206. Maruyama, I. N., and S. Brenner. A phorbol ester/diacylglycerol‐binding protein encoded by the unc‐13 gene of Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 88: 5729–5733, 1991.
 207. Masmoudi, A., G. Labourdette, M. Mersel, F. L. Huang, K. Huang, G. Vincendon, and A. N. Malviya. Protein kinase C located in rat liver nuclei. Partial purification and biochemical and immunocytochemical characterization. J. Biol. Chem. 264: 1172–1179, 1989.
 208. McCaffrey, P. G., C. Luo, T. K. Kerppola, J. Jain, T. M. Badalian, A. M. Ho, E. Burgeon, W. S. Lane, J. N. Lambert, T. Curran, G. L. Verdine, A. Rao, and P. G. Hogan. Isolation of the cyclosporin‐sensitive T cell transcription factor NFATp. Science 262: 750–754, 1993.
 209. McCaffrey, P. G., B. A. Perrino, T. R. Soderling, and A. Rao. NFATp, a T lymphocyte DNA‐binding protein that is a target of calcineurin and immunosuppressive drugs. J. Biol. Chem. 268: 3747–3752, 1993.
 210. Merat, D. L., Z. Y. Hu, T. E. Carter, and W. Y. Cheung. Bovine brain calmodulin‐dependent protein phosphatase. J. Biol. Chem. 260: 11053–11059, 1985.
 211. Milan, D., J. Griffith, M. Su, E. R. Price, and F. McKeon. The latch region of calcineurin B is involved in both immuno‐suppressant‐immunophilin complex docking and phosphatase activation. Cell 79: 437–447, 1994.
 212. Millar, J. B., J. Blevitt, L. Gerace, S. Sadhu, C. Featherstone, and P. Russell. p55cdc25 is a nuclear protein required for the initiation of mitosis in human cells. Proc. Natl. Acad. Sci. U.S.A. 10500–10504, 1991.
 213. Mischak, H., J. Goodnight, W. Kolch, G. Martiny‐Baron, C. Schaechtle, M. G. Kazanietz, P. M. Blumberg, J. H. Pierce, and J. F. Mushinski. Overexpression of protein kinase C‐δ and – in NIH 3T3 cells induced opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem. 268: 6090–6096, 1993.
 214. Mochly‐Rosen, D., H. Khaner, and J. Lopez. Identification of intracellular receptor proteins for activated protein kinase C. Proc. Natl. Acad. Sci. U.S.A. 88: 3997–4000, 1991.
 215. Mochly‐Rosen, D., H. Khaner, J. Lopez, and B. L. Smith. Intracellular receptors for activated protein kinase C. J. Biol. Chem. 266: 14866–14868, 1991.
 216. Morgan, D. O. Cell cycle control in normal and neoplastic cells. Curr. Opin. Genet. Dev. 2: 33–37, 1992.
 217. Morgan, D. O. Principles of cdk regulation. Nature 374: 131–134, 1995.
 218. Morgan, D. O., and H. L. De Bondt Protein kinase regulation: insights from crystal structure analysis. Curr. Opin. Cell Biol. 6: 239–246, 1994.
 219. Mori, T., Y. Takai, B. Yu, J. Takahashi, Y. Nishizuka, and T. Fujikura. Specificity of the fatty acyl moieties of diacylglycerol for the activation of calcium‐activated, phospholipid‐dependent protein kinase. J. Biochem. (Tokyo) 91: 427–431, 1982.
 220. Mueller, P. R., T. R. Coleman, A. Kumagai, and W. G. Dunphy. Myt1: a membrane‐associated inhibitory kinase that phosphorylates cdc2 on both threonine‐14 and tyrosine‐15. Science 270: 86–90, 1995.
 221. Mukai, H., C. D. Change, H. Tanaka, A. Ito, T. Kuno, and C. Tanaka. cDNA cloning of a novel testis‐specific calcineurin B‐like protein. Biochem. Biophys. Res. Commun. 179: 1325–1330, 1991.
 222. Muramatsu, T., P. R. Giri, S. Higuchi, and R. L. Kincaid. Molecular cloning of a calmodulin‐dependent phosphatase from murine testis: identification of a developmentally expressed nonneural enzyme. Proc. Natl. Acad. Sci. U.S.A. 89: 529–533, 1992.
 223. Muramatsu, T. Kincaid. Molecular cloning of a full‐length cDNA encoding the catalytic subunit of human calmodulin‐dependent protein phosphatase (calcineurin Aα). Biochim. Biophys. Acta 1178: 117–120, 1993.
 224. Murray, A. W. Cyclin‐dependent kinases: regulators of the cell cycle and more. Curr. Biol. 1: 191–195, 1994.
 225. Murray, A. W., M. J. Solomon, and M. W. Kirschner. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339: 280–286, 1989.
 226. Nakamura, S., and Y. Nishizuka. Lipid mediators and protein kinase C activation for the intracellular signaling network. J. Biochem. (Tokyo) 115: 1029–1034, 1994.
 227. Nakanishi, H., K. A. Brewer, and J. H. Exton. Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5‐trisphosphate. J. Biol. Chem. 268: 13–16, 1993.
 228. Nakaoka, T., N. Kojima, T. Ogita, and S. Tsuji. Characterization of the phosphatidylserine‐binding region of rat MARCKS (myristoylated, alanine‐rich protein kinase C substrate). J. Biol. Chem. 270: 12147–12151, 1995.
 229. Naor, Z., J. Zer, H. Zakut, and J. Hermon. Characterization of pituitary calcium‐activated, phospholipid‐dependent protein kinase: redistribution by gonadotropin‐releasing hormone. Proc. Natl. Acad. Sci. U.S.A. 82: 8203–8207, 1985.
 230. Nargang, C. E., D. A. Bottorff, and K. Adachi. Isolation and characterization of a cDNA clone coding for the calcium‐binding subunit of calcineurin from bovine brain: an identical amino acid sequence to the human protein. DNA Seq. 4: 313–318, 1994.
 231. Nigg, E. A. Targets of cyclin‐dependent protein kinases. Curr. Opin. Cell Biol. 5: 187–193, 1993.
 232. Nishida, E., and Y. Gotoh. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends. Biochem. Sci. 18: 128–132, 1993.
 233. Nishizuka, Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334: 661–665, 1988.
 234. Nishizuka, Y. Membrane phospholipid degradation and protein kinase C for cell signalling. Neurosci. Res. 15: 3–5, 1992.
 235. Northrup, J. P., S. N. Ho, L. Chen, D. J. Thomas, L. A. Timmerman, G. P. Nolan, A. Admon, and G. R. Crabtree. NF‐AT components define a family of transcription factors targeted in T‐cell activation. Nature 369: 497–502, 1994.
 236. O'Keefe, S. J., J. Tamura, R. L. Kincaid, M. J. Tocci, and E. A. O'Neill. FK506 and CsA‐sensitive activation of the interleukin‐2 promoter by calcineurin. Nature 357: 692–695, 1992.
 237. Ogg, S., B. Gabrielli, and H. Piwnica‐Worms. Purification of a serine kinase that associates with and phosphorylates human cdc25C on serine 216. J. Biol. Chem. 269: 30461–30469, 1994.
 238. Ohtsubo, M., and J. M. Roberts. Cyclin‐dependent regulation of G1 in mammalian fibroblasts. Science 259: 1908–1912, 1993.
 239. Ohtsubo, M., A. M. Theodoras, J. Schumacker, J. M. Roberts, and M. Pagano. Human cyclin E, a nuclear protein essential for the G1‐to‐S phase transition. Mol. Cell. Biol. 15: 2612–2624, 1995.
 240. Olivier, A. R., S. C. Kiley, C. Pears, D. Schaap, S. Jaken, and P. J. Parker. Protein kinase C‐delta and ‐epsilon: a functional appraisal. Biochem. Soc. Trans. 20: 603–607, 1992.
 241. Olivier, A. R., and P. J. Parker. Expression and characterization of protein kinase C‐δ. Eur. J. Biochem. 200: 805–810, 1991.
 242. Olivier, A. R., and P. J. Parker. Bombesin, platelet‐derived growth factor, and diacylglycerol induce selective membrane association and down‐regulation of protein kinase C isotypes in Swiss 3T3 cells. J. Biol. Chem. 269: 2758–2763, 1994.
 243. Ono, Y., T. Fujii, K. Igarashi, T. Kuno, C. Tanaka, U. Kikkawa, and Y. Nishizuka. Phorbol ester binding to protein kinase C requires a cysteine‐rich zinc‐finger‐like sequence. Proc. Natl. Acad. Sci. U.S.A. 86: 4868–4871, 1989.
 244. Osada, S., K. Mizuno, T. C. Saido, Y. Akita, K. Suzuki, T. Kuroki, and S. Ohno. A phorbol ester receptor/protein kinase, nPKC, a new member of the protein kinase C family predominantly expressed in lung and skin. J. Biol. Chem. 265: 22434–22440, 1990.
 245. Osada, S., K. Mizuno, T. C. Saido, K. Suzuki, T. Kuroki, and S. Ohno. A new member of the protein kinase C family, nPKC, predominantly expressed in skeletal muscle. Mol. Cell. Biol. 12: 3930–3938, 1992.
 246. Pagano, M., R. Pepperkok, F. Verde, W. Ansorge, and G. Draetta. Cyclin A is required at two points in the human cell cycle. EMBO J. 11: 961–971, 1992.
 247. Pallas, D. C., H. Fu, L. D. Cripe, R. J. Collier, and T. M. Roberts. Association of the polyoma virus middle tumor antigen with 14–3–3 proteins. Science 265: 535–537, 1994.
 248. Pallen, C. J., and J. H. Wang. Calmodulin‐stimulated dephosphorylation of p‐nitrophenylphosphate and free phosphotyrosine by calcineurin. J. Biol. Chem. 258: 8550–8553, 1983.
 249. Papadopoulos, V. P., and P. F. Hall. Isolation and characterization of protein kinase C from Y‐1 adrenal cell cytoskeleton. J. Cell Biol. 108: 553–567, 1989.
 250. Park, J., N. R. Yaseen, P. G. Hogan, A. Rao, and S. Sharma. Phosphorylation of the transcription factor NFATp inhibits its DNA binding activity in cyclosporin A‐treated human B and T cells. J. Biol. Chem. 270: 20653–20659, 1995.
 251. Parker, L. L., and H. Piwnica‐Worms. Inactivation of the p34cdc2‐cyclin B complex by the human WEE1 tyrosine kinase. Science 257: 1955–1957, 1992.
 252. Parker, L. L., S. A. Walter, P. G. Young, and H. Piwnica‐Worms. Phosphorylation and inactivation of the mitotic inhibitor Wee1 by the nim1/cdr1 kinase. Nature 363: 736–738, 1993.
 253. Pazin, M. J., and L. T. Williams. Triggering signaling cascades by receptor tyrosine kinases. Trends Biochem. Sci. 17: 374–378, 1992.
 254. Peeper, D. S., L. L. Parker, M. E. Ewen, M. Toebes, F. L. Hall, M. Xu, A. Zantema, A. J. van der Eb, and H. Piwnica‐Worms. A‐ and B‐type cyclins differentially modulate substrate specificity of cyclin‐cdk complexes. EMBO J. 12: 1947–1954, 1993.
 255. Perrino, B. A., Y. Fong, D. A. Brickey, Y. Saitoh, Y. Ushio, K. Fukunaga, E. Miyamoto, and T. R. Soderling. Characterization of the phosphatase activity of a baculovirus‐expressed calcineurin A isoform. J. Biol. Chem. 267: 15965–15969, 1992.
 256. Perrino, B. A., L. Y. Ng, and T. R. Soderling. Calcium regulation of calcineurin phosphatase activity by its B subunit and calmodulin. J. Biol. Chem. 270: 340–346, 1995.
 257. Pessin, M. S., and D. M. Raben. Molecular species analysis of 1,2‐diacylglycerides stimulated by alpha‐thrombin in cultured fibroblasts. J. Biol. Chem. 264: 8729–8738, 1989.
 258. Peter, M., and I. Herskowitz. Joining the complex: cyclin‐dependent kinase inhibitory proteins and the cell cycle. Cell 79: 181–184, 1994.
 259. Pines, J. Cyclins and cyclin‐dependent kinases: take your partners. Trends Biochem. Sci. 18: 195–197, 1993.
 260. Pines, J., and T. Hunt. Molecular cloning and characterization of the mRNA for cyclin from sea urchin eggs. EMBO J. 6: 2987–2995, 1987.
 261. Polyak, K., J. Kato, M. J. Solomon, C. J. Scherr, J. Massague, J. M. Roberts, and A. Koff. p27KIP1, a cyclin‐Cdk inhibitor, links transforming growth factor‐β and contact inhibition to cell cycle arrest. Genes Dev. 8: 9–22, 1994.
 262. Polyak, K., M. Lee, H. Erdjument‐Bromage, A. Koff, J. M. Roberts, P. Tempst, and J. Massague. Cloning of p27Kip1, a cyclin‐dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66, 1994.
 263. Poon, R.Y.C., and T. Hunter. Dephosphorylation of cdk2 Thr160 by the cyclin‐dependent kinase interacting phosphatase KAP in the absence of cyclin. Science 270: 90–93, 1995.
 264. Poon, Y.C.R., K. Yamahita, J. P. Adamczewski, T. Hunt, and J. Shuttleworth. The cdc2‐related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J. 12: 3123–3132, 1993.
 265. Quest, A.F.G., E.S.G. Bardes, and R. M. Bell. A phorbol ester binding domain of protein kinase C. J. Biol. Chem. 269: 2953–2960, 1994.
 266. Raben, D. M., M. B. Jarpe, and K. L. Leach. Nuclear lipid metabolism in NEST: nuclear envelope signal transduction. J. Membr. Biol. 142: 1–7, 1994.
 267. Rao, A. NFATp: a transcription factor required for the coordinate induction of several cytokine genes. Immunol. Today 15: 274–281, 1994.
 268. Rao, A. NFATp, a cyclosporin‐sensitive transcription factor implicated in cytokine gene induction. J. Leukocyte Biol. 57: 536–542, 1995.
 269. Reuther, G. W., H. Fu, L. D. Cripe, R. J. Collier, and A. M. Pendergast. Association of the protein kinases c‐Bcr and Bcr‐Abl with proteins of the 14–3–3 family. Science 266: 129–133, 1994.
 270. Roach, P. Multisite and hierarchal protein phosphorylation. J. Biol. Chem. 266: 14139–14142, 1991.
 271. Ron, D., C. Chen, J. Caldwell, L. Jamieson, E. Orr, and D. Mochly‐Rosen. Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc. Natl. Acad. Sci. U.S.A. 91: 839–843, 1994.
 272. Ron, D., J. Luo, and D. Mochly‐Rosen. C2 region‐derived peptides inhibit translocation and function of β protein kinase C in vivo. J. Biol. Chem. 270: 24180–24187, 1995.
 273. Rosenmund, C., D. W. Carr, S. E. Bergeson, G. Nilaver, J. D. Scott, and G. L. Westbrook. Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368: 853–855, 1994.
 274. Rosoff, P. M., N. Savage, and C. A. Dinarello. Interleukin‐1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism. Cell 54: 73–81, 1988.
 275. Roy, R., J. P. Adamczewski, T. Seroz, W. Vermeulen, J. Tassan, L. Schaeffer, E. A. Nigg, J.H.J. Hoejmakers, and J. Egly. The MO15 cell cycle kinase is associated with the TFIIH transcription‐DNA repair factor. Cell 79: 1093–1101, 1994.
 276. Ruderman, J. V. MAP kinase and the activation of quiescent cells. Curr. Biol. 5: 207–213, 1993.
 277. Ruff, V. A., and K. L. Leach. Direct demonstration of NFATp dephosphorylation and nuclear localization in activated HT‐2 cells using a specific NFATp polyclonal antibody. J. Biol. Chem. 270: 22602–22607, 1995.
 278. Russell, P., and P. Nurse. cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45: 145–153, 1986.
 279. Sadhu, K., S. I. Reed, H. Richardson, and P. Russell. Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. Proc. Natl. Acad. Sci. U.S.A. 87: 5139–5143, 1990.
 280. Said, T. K., and D. Medina. Cell cyclins and cyclin‐dependent kinase activities in mouse mammary tumor development. Carcinogenesis 16: 823–830, 1995.
 281. Sarafian, T., L. Pradel, J. Henry, D. Aunis, and M. Bader. The participation of annexin II (calpactin I) in calcium‐evoked exocytosis requires protein kinase C. J. Cell Biol. 114: 1135–1147, 1991.
 282. Schaap, D., and P. J. Parker. Expression, purification, and characterization of protein kinase C‐. J. Biol. Chem. 265: 7310–7307, 1990.
 283. Schaap, D., P. J. Parker, A. Bristol, R. Kriz, and J. Knopf. Unique substrate specificity and regulatory properties of PKC‐: a rationale for diversity. FEBS Lett. 243: 351–357, 1989.
 284. Selbie, L. A., C. Schmitz‐Peiffer, Y. Sheng, and T. J. Biden. Molecular cloning and characterization of PKC iota, an atypical isoform of protein kinase C derived from insulin‐secreting cells. J. Biol. Chem. 268: 24296–24302, 1993.
 285. Shenolikar, S. Protein serine/threonine phosphatases‐–new avenues for cell regulation. Annu. Rev. Cell Biol. 10: 55–86, 1994.
 286. Sherr, C. J. Mammalian G1 cyclins. Cell 73: 1059–1065, 1993.
 287. Sherr, C. J. Growth factor‐regulated G1 cyclins. Stem Cells 12: 47–57, 1994.
 288. Sherr, C. J. G1 phase progression: cycling on cue. Cell 79: 551–555, 1994.
 289. Sheu, F., R. M. Marais, P. J. Parker, N. G. Bazan, and A. Routtenberg. Neuron‐specific protein F1/GAP‐43 shows substrate specificity for the beta subtype of protein kinase C. Biochem. Biophys. Res. Commun. 171: 1236–1243, 1990.
 290. Shinomura, T., Y. Asaoka, M. Oka, K. Yoshida, and Y. Nishizuka. Synergistic action of diacylglycerol and unsaturated fatty acid for protein kinase C activation: its possible implications. Proc. Natl. Acad. Sci. U.S.A. 88: 5149–5153, 1991.
 291. Soderling, T. R. Protein kinases. J. Biol. Chem. 265: 1823–1826, 1990.
 292. Soderling, T. R. Protein kinases and phosphatases: regulation by autoinhibitory domains. Biotechnol. Appl. Biochem. 18: 185–200, 1993.
 293. Solomon, M. J., J. W. Harper, and J. Shuttleworth. CAK, the p34cdc2 activating kinase, contains a protein identical or closely related to p40. EMBO J. 12: 3133–3142, 1993.
 294. Solomon, M. J., T. Lee, and M. W. Kirschner. Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol. Biol. Cell 3: 13–27, 1992.
 295. Stabel, S. Protein kinase C‐–an enzyme and its relatives. Semin. Cancer Biol. 5: 277–284, 1994.
 296. Stabel, S., and P. J. Parker. Protein kinase C. Pharmacol. Ther. 51: 71–95, 1991.
 297. Stemmer, P. M., and C. B. Klee. Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B. Biochemistry 33: 6859–6866, 1994.
 298. Stewart, A. A., T. S. Ingebritsen, A. Manalan, C. B. Klee, and P. Cohen. Discovery of a Ca2+‐ and calmodulin‐dependent protein phosphatase. FEBS Lett. 137: 80–84, 1982.
 299. Strausfield, U., A. Fernandez, J. Capony, F. Girard, N. Lautredou, J. Derancourt, J. Labbe, and N.J.C. Lamb. Activation of p34cdc2 protein kinase by microinjection of human cdc25c into mammalian cells. J. Biol. Chem. 269: 5989–6000, 1994.
 300. Strausfeld, U., J. C. Labbe, D. Fesquet, J. C. Cavadore, A. Picard, K. Sadhu, P. Russell, and M. Doree. Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human cdc25 protein. Nature 351: 242–245, 1991.
 301. Sun, H., C. H. Charles, L. F. Lau, and N. K. Tonks. MKP‐1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75: 487–493, 1993.
 302. Sun, H., and N. K. Tonks. The coordinated action of protein tyrosine phosphatases and kinases in cell signaling. Trends Biochem. Sci. 19: 480–484, 1994.
 303. Tallant, E. A., and W. Y. Cheung. Calmodulin‐dependent protein phosphatase: a developmental study. Biochemistry 22: 3630–3635, 1983.
 304. Tallant, E. A., and W. Y. Cheung. Characterization of bovine brain calmodulin‐dependent protein phosphatase. Arch. Biochem. Biophys. 232: 269–279, 1984.
 305. Tallant, E. A., and W. Y. Cheung. Calmodulin‐dependent protein phosphatase. In: Calcium and Cell Function, edited by W. Y. Cheung Orlando, FL: Academic, 1986, p. 71–111.
 306. Tanaka, T., H. Ohta, K. Kanda, H. Hidaka, and K. Sobue. Phosphorylation of high Mr caldesmon by protein kinase‐C modulates the regulatory function of this protein on the interaction between actin and myosin. Eur. J. Biochem. 188: 495–500, 1990.
 307. Tang, Z., T. R. Coleman, and W. G. Dunphy. Two distinct mechanisms for negative regulation of the Wee1 protein kinase. EMBO J. 12: 3427–3436, 1993.
 308. Taylor, S. S., D. R. Knighton, J. Zheng, J. M. Sowadski, C. S. Gibbs, and M. J. Zoller. A template for the protein kinase family. Trends Biochem. Sci. 18: 84–89, 1993.
 309. Thomas, T. P., H. S. Talwar, and W. B. Anderson. Phorbol ester‐mediated association of protein kinase C to the nuclear fraction in NIH 3T3 cells. Cancer Res. 48: 1910–1919, 1988.
 310. Tonks, N. K., C. D. Diltz, and E. H. Fischer. Purification of the major protein‐tyrosine‐phosphatase of human placenta. J. Biol. Chem. 263: 6722–6730, 1988.
 311. Toyoshima, H., and T. Hunter. p27, a novel inhibitor of G1 cyclin‐cdk protein kinase activity, is related to p21. Cell 78: 67–74, 1994.
 312. Ueki, K., and R. L. Kincaid. Interchangeable associations of calcineurin regulatory subunit isoforms with mammalian and fungal catalytic subunits. J. Biol. Chem. 268: 6554–6559, 1993.
 313. Ueki, K., T. Muramatsu, and R. L. Kincaid. Structure and expression of two isoforms of the murine calmodulin‐dependent protein phosphatase regulatory subunit (calcineurin B). Biochem. Biophys. Res. Commun. 187: 537–543, 1992.
 314. Ullman, K. S., J. P. Northrup, C. L. Verweij, and G. R. Crabtree. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Annu. Rev. Immunol. 8: 421–452, 1990.
 315. Ullrich, A., and J. Schlessinger. Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212, 1990.
 316. van den Heuvel, S., and E. Harlow. Distinct roles for cyclin‐dependent kinases in cell cycle control. Science 262: 2050–2054, 1993.
 317. Villa‐Moruzzi, E. Activation of the cdc25c phosphatase in mitotic HeLa cells. Biochem. Biophys. Res. Commun. 196: 1248–1254, 1993.
 318. Wadzinski, B. E., L. E. Heasley, and G. L. Johnson. Multiplicity of protein serine‐threonine phosphatases in PC12 pheochromocytoma and FTO‐2B hepatoma cells. J. Biol. Chem. 265: 21504–21508, 1990.
 319. Walker, D. H., and J. L. Maller. Role of cyclin A in the dependence of mitosis on completion of DNA replication. Nature 354: 314–317, 1991.
 320. Walker, S. D., N. R. Murray, D. J. Burns, and A. P. Fields. Protein kinase C chimeras: catalytic domains of α and βII protein kinase C contain determinants for isotype‐specific function. Proc. Natl. Acad. Sci. U.S.A. 92: 9156–9160, 1995.
 321. Wallace, R. W., E. A. Tallant, and W. Y. Cheung. High levels of a heat‐labile calmodulin‐binding protein (CaM‐BP80) in bovine neostriatum. Biochemistry 19: 1831–1837, 1980.
 322. Walton, K. M., and J. E. Dixon. Protein tyrosine phosphatases. Annu. Rev. Biochem. 62: 101–120, 1993.
 323. Ward, Y., S. Gupta, P. Jensen, M. Wartmann, R. J. Davis, and K. Kelly. Control of MAP kinase activation by the mitogen‐induced threonine/tyrosine phosphatase PAC1. Nature 367: 651–654, 1994.
 324. Waseem, A., and H. C. Palfrey. Identification and protein kinase C‐dependent phosphorylation of α‐adducin in human fibroblasts. J. Cell Sci. 96: 93–98, 1990.
 325. Watanabe, N., M. Broome, and T. Hunter. Regulation of the human WEE1 Hu cdk tyrosine 15‐kinase during the cell cycle. EMBO J. 14: 1878–1891, 1995.
 326. Watanabe, Y., B. A. Perrino, B. H. Chang, and T. R. Soderling. Identification in the calcineurin A subunit of the domain that binds the regulatory B subunit. J. Biol. Chem. 270: 456–460, 1995.
 327. Weinstein, I. B., P. B. Fisher, A. Mufson, and H. Yamasaki. Action of phorbol esters in cell culture: mimicry of transformation, altered differentiation, and effects on cell membranes. J. Supramol. Struct. 12: 195–208, 1979.
 328. Wetsel, W. C., W. A. Khan, I. Merchenthaler, H. Rivera, A. E. Halpern, H. M. Phung, A. Negro‐Vilar, and Y. A. Hannun. Tissue and cellular distribution of the extended family of protein kinase C isoenzymes. J. Cell Biol. 117: 121–133, 1992.
 329. Wood, J. G., R. W. Wallace, J. N. Whitaker, and W. Y. Cheung. Immunocytochemical localization of calmodulin and a heat‐labile calmodulin‐binding protein (CaM‐BP80) in basal ganglia of mouse brain. J. Cell. Biol. 84: 66–76, 1980.
 330. Wooten, M. W., and R. W. Wrenn. Phorbol ester induces intracellular translocation of phospholipid/Ca2+‐dependent protein kinase and stimulates amylase secretion in isolated pancreatic acini. FEBS Lett. 171: 183–186, 1984.
 331. Wright, T. M., L. A. Rangan, H. S. Shin, and D. M. Raben. Kinetic analysis of 1,2‐diacylglycerol mass levels in cultured fibroblasts. Comparison of stimulation by alpha‐thrombin and epidermal growth factor. J. Biol. Chem. 263: 9374–9380, 1988.
 332. Wright, T. M., H. S. Shin, and D. M. Raben. Sustained increase in 1,2‐diacylglycerol precedes DNA synthesis in epidermal‐growth‐factor‐stimulated fibroblasts. Evidence for stimulated phosphatidylcholine hydrolysis. Biochem. J. 267: 501–507, 1990.
 333. Wu, J., J. K. Harrison, L. A. Vincent, C. Haystead, T.A.J. Haystead, H. Michel, D. F. Hunt, K. R. Lynch, and T. W. Sturgill. Molecular structure of a protein‐tyrosine/threonine kinase activating p42 mitogen‐activated protein (MAP) kinase: MAP kinase kinase. Proc. Natl. Acad. Sci. U.S.A. 90: 173–177, 1993.
 334. Wu, J., H. Michel, P. Dent, T. Haystead, D. F. Hunt, and T. W. Sturgill. Activation of MAP kinase by a dual specificity tyr/thr kinase. Adv. Second Messenger Phosphoprotein Res. 28: 219–225, 1993.
 335. Wu, L., and P. Russell. Nim1 kinase promotes mitosis by inactivating Wee1 tyrosine kinase. Nature 363: 738–741, 1993.
 336. Wu, L., A. Yee, L. Liu, D. Carbonaro‐Hall, N. Venkatesan, V. T. Tolo, and F. L. Hall. Molecular cloning of the human CAK1 gene encoding a cyclin‐dependent kinase‐activating kinase. Oncogene 9: 2089–2096, 1994.
 337. Yang, Z., N. D. Perkins, T. Ohno, E. Nabel, and G. J. Nabel. The p21 cyclin‐dependent kinase inhibitor suppresses tumorigenicity in vivo. Nature Med. 1: 1052–1056, 1995.
 338. Yazdanbakhsh, K., J. Choi, Y. Li, L. F. Lau, and Y. Choi. Cyclosporin A blocks apoptosis by inhibiting the DNA binding activity of the transcription factor Nur77. Proc. Natl. Acad. Sci. U.S.A. 92: 437–441, 1995.
 339. Yoshida, K., Y. Asaoka, and Y. Nishizuka. Platelet activation by simultaneous actions of diacylglycerol and free unsaturated fatty acids. Proc. Natl. Acad. Sci. U.S.A. 89: 6443–6446, 1992.
 340. Young, S., P. J. Parker, A. Ullrich, and S. Stabel. Down‐regulation of protein kinase C is due to an increased rate of degradation. Biochem. J. 244: 775–779, 1987.
 341. Zhang, G., M. G. Kazanietz, P. M. Blumberg, and J. H. Hurley. Crystal structure of the Cys2 activator‐binding domain of protein kinase Cδ in complex with phorbol ester. Cell 81: 917–924, 1995.
 342. Zhao, Y., Y. Tozawa, R. Iseki, M. Mukai, and M. Iwata. Calcineurin activation protects T cells from glucocorticoid‐induced apoptosis. J. Immunol. 154: 6346–6354, 1995.
 343. Zheng, X., and J. V. Ruderman. Functional analysis of the P box, a domain in cyclin B required for the activation of cdc25. Cell 75: 155–164, 1993.
 344. Zhou, G., J. M. Denu, L. Wu, and J. E. Dixon. The catalytic role of Cys124 in the dual specificity phosphatase VHR. J. Biol. Chem. 269: 28084–28090, 1994.

Contact Editor

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

* Required Field

How to Cite

Karen L. Leach. Protein Kinases and Phosphatases in Cellular Signaling. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 225-253. First published in print 1998. doi: 10.1002/cphy.cp070110