Comprehensive Physiology Wiley Online Library

Mechanisms of Transmembrane Signaling

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Signal Transduction via Heterotrimeric GTP‐Binding Proteins
1.1 G Protein Coupled Receptors (GCRs)
1.2 Heterotrimeric GTP‐Binding Proteins (G Proteins)
1.3 Diseases Linked to GCRs and G Proteins
1.4 Examples of G Protein–Regulated Effectors and Signaling Pathways
2 Signal Transduction via Receptor Tyrosine Kinases
2.1 Introduction to Receptor Tyrosine Kinases (RTKs)
2.2 Initial Steps of RTK Signal Transduction
2.3 Ras Activation by RTK
2.4 Ras Stimulates the MAPK Pathway Via Its Effector, Raf‐1
2.5 RTK Signaling Mechanisms Are Used by Other Receptor Families
3 Mitogenic Crosstalk: GCRs, RTKs, and the MAPK Pathway
3.1 A GCR Induces Tyrosine Phosphorylation of SHC
3.2 Ras Activation by Gβγ
3.3 Gβγ Stimulation of MAPK in Yeast
3.4 Gαi Stimulation of a MEK Kinase in Rat‐1a Cells
3.5 GCR‐Mediated Inhibition of Mitogenic Signaling
4 Conclusion
Figure 1. Figure 1.

Diversity of ligands for G protein—coupled receptors.

Figure 2. Figure 2.

Proposed topology of β2‐adrenergic receptor, model for GCR family. CHO indicates N‐glycosylation sites of β2‐adrenergic receptor. Domains N‐III and C‐III have been implicated in specifying G protein interactions in several different GCRs. Membrane‐proximal portion of carboxyl‐terminus likely forms fourth intracellular loop by virtue of palmitic acid attachment.

Figure 3. Figure 3.

G protein activity cycle. Binding of agonist (A) to G protein—coupled receptor induces conformational change in receptor which promotes release of GDP from heterotrimeric G protein αβγ complex. In presence of Mg2+, GTP can bind Gα, presumably causing dissociation of G protein from receptor, and Gα‐GTP from Gβγ. Intrinsic GTPase activity of Gα hydrolyzes GTP to GDP and Gαβγ heterotrimer is reformed.

Figure 4. Figure 4.

Evolutionary tree of mammalian Gα.

Modified from Simon et al. and used with permission
Figure 5. Figure 5.

A. Linear map of Gα functional domains. B. Crystal structure of Gαi1 bound to GTPγS; 32 amino‐terminal and 11 carboxyl‐terminal residues were not resolved. Bound nucleotide and Mg2+ (ball‐and‐stick model) are seen clearly in structure. GTP binding results in aggregation and protrusion of three “Switch” regions: Switch I=Linker 2. Switch II = α2. Switch III = domain linking β4 and α3. Switch regions were identified by comparison of structures of FTP and GDP‐bound forms of Gαt. Three‐dimensional picture of domain (β1: unresolved amino‐terminus) implicated by proteolysis and antibody studies in interaction with Gβγ is not available. Receptor interaction is probably mediated by structures in carboxyl‐terminus (β6, α5). Evidence suggests that exposed regions α2/β4, α3/β5, and α4/ β6 are involved in effector interactions.

From Coleman et al. , Lambright et al. , Noel et al. , figure used with permission from Dr. A. G. Gilman
Figure 6. Figure 6.

Simplified representation of phototransduction system. A photon (hv) stimulates rhodopsin (Rh), which activates G protein transducin (Gαtβγ). Gαt‐GTP stimulates cyclic GMP phosphodiesterase (PDE), which decreases intracellular cGMP concentrations. Decreased cGMP closes a Ca2+‐permeable ion channel, decreasing intracellular Ca2+ levels, which inhibits the release of neurotransmitter at the photoreceptor synapse. Regulatory mechanisms are discussed in text.

Modified from Koutalos and Yau and used with permission
Figure 7. Figure 7.

Topology of mammalian adenylyl cyclase. Two homologous cytoplasmic domains (thick lines) are flanked by two membrane‐spanning domains containing six putative α‐helices each.

Figure 8. Figure 8.

Crosstalk in receptor coupling to adenylyl cyclase isoforms.

Modified from Pieroni et al. and used with permission
Figure 9. Figure 9.

Preferential substrate for family of phospholipases is phosphoglyceride with either ethanolamine, choline, or inositol group in R position.

Figure 10. Figure 10.

Stimulation of many transmembrane receptors leads to activation of phospholipases. Many important second messengers are generated from action of these phospholipases, including AA = arachadonic acid, InsP3 = inositol‐1,4,5‐trisphosphate, and DAG = diacylglycerol.

Figure 11. Figure 11.

Structural alignment of members of PLC (phospholipase C) subfamilies. X and Y denote critical catalytic domains found within all PLC isoforms. SH2 and SH3 domains, located in PLC‐γ isoforms, interact with activated tyrosine‐kinase‐linked receptors and effector molecules, respectively. EF‐hand is a putative Ca2+‐binding motif located exclusively in PLC‐δ isoforms.

Figure 12. Figure 12.

IKACh in inside‐out patches from atrial myocyes is activated by Gβγ and GTPγS. GTPγS activation of IKACh occurring by activation of endogenous G proteins, completely inhibited by purified Gα‐GDP, either bovine brain Gα or recombinant Gα13.IKACh is restimulated by a molar excess of Gβγ (from bovine brain or recombinant Gβ2γ5).

Figure 13. Figure 13.

Schematic depiction of families of RTKs.

Figure 14. Figure 14.

General scheme of signal transduction by RTKs. Ligand binding leads to RTK dimerization, which activates RTK tyrosine kinase and leads to autophosphorylation. Binding of SH2 domains of intracellular proteins to specific receptor phosphotyrosine residues mediates signaling through ligand‐bound receptor.

Figure 15. Figure 15.

SH2‐ and SH3‐containing proteins. SH2 domains are depicted in linear amino acid sequence as black box. SH3 domains are depicted by boxes labeled “3.” PTPase = protein tyrosine phosphatase, PLC = phospholipase C, GAP = GTPase‐activating protein, PI3K = phosphatidylinositol‐3‐OH kinase, and DBL = Dbl homology.

Modified from Pawson and Gish and used with permission
Figure 16. Figure 16.

SH2‐containing proteins bind to specific phosphotyrosine residues of activated PDGF receptor.

Modified from Pawson and Schlessinger and used with permission
Figure 17. Figure 17.

Ras cycle. GAP (GTPase‐activating proteins) and GDS (GDP‐dissociating stimulators) catalyze activation and inactivation of ras, respectively.

Figure 18. Figure 18.

Different RTKs use different methods to stimulate ras. After binding ligand (not shown), RTK phosphorylate specific tyrosines on themselves or other proteins. These phosphotyrosines form binding sites for SH2 domains of proteins that can recruit GRB‐2/SOS.

Figure 19. Figure 19.

RTK signaling pathways in different organisms.

Figure 20. Figure 20.

Mitogen‐activated protein kinase (MAPK) pathway. Catalytically active proteins are shown in ovals; inactive forms are shown in rectangles. (Described in the section Ras Stimulates the MAPK Pathway Via Its Effector, Raf‐1)

Figure 21. Figure 21.

Aspects of RTK signaling paradigm are used by other families of receptors.

Figure 22. Figure 22.

Regulation of MAPK pathway by G protein–coupled receptors.

Figure 23. Figure 23.

Pheromone receptor stimulation of MAPK in yeast. Three possible pathways are shown, supported by genetic analysis of S. cerevisiae.



Figure 1.

Diversity of ligands for G protein—coupled receptors.



Figure 2.

Proposed topology of β2‐adrenergic receptor, model for GCR family. CHO indicates N‐glycosylation sites of β2‐adrenergic receptor. Domains N‐III and C‐III have been implicated in specifying G protein interactions in several different GCRs. Membrane‐proximal portion of carboxyl‐terminus likely forms fourth intracellular loop by virtue of palmitic acid attachment.



Figure 3.

G protein activity cycle. Binding of agonist (A) to G protein—coupled receptor induces conformational change in receptor which promotes release of GDP from heterotrimeric G protein αβγ complex. In presence of Mg2+, GTP can bind Gα, presumably causing dissociation of G protein from receptor, and Gα‐GTP from Gβγ. Intrinsic GTPase activity of Gα hydrolyzes GTP to GDP and Gαβγ heterotrimer is reformed.



Figure 4.

Evolutionary tree of mammalian Gα.

Modified from Simon et al. and used with permission


Figure 5.

A. Linear map of Gα functional domains. B. Crystal structure of Gαi1 bound to GTPγS; 32 amino‐terminal and 11 carboxyl‐terminal residues were not resolved. Bound nucleotide and Mg2+ (ball‐and‐stick model) are seen clearly in structure. GTP binding results in aggregation and protrusion of three “Switch” regions: Switch I=Linker 2. Switch II = α2. Switch III = domain linking β4 and α3. Switch regions were identified by comparison of structures of FTP and GDP‐bound forms of Gαt. Three‐dimensional picture of domain (β1: unresolved amino‐terminus) implicated by proteolysis and antibody studies in interaction with Gβγ is not available. Receptor interaction is probably mediated by structures in carboxyl‐terminus (β6, α5). Evidence suggests that exposed regions α2/β4, α3/β5, and α4/ β6 are involved in effector interactions.

From Coleman et al. , Lambright et al. , Noel et al. , figure used with permission from Dr. A. G. Gilman


Figure 6.

Simplified representation of phototransduction system. A photon (hv) stimulates rhodopsin (Rh), which activates G protein transducin (Gαtβγ). Gαt‐GTP stimulates cyclic GMP phosphodiesterase (PDE), which decreases intracellular cGMP concentrations. Decreased cGMP closes a Ca2+‐permeable ion channel, decreasing intracellular Ca2+ levels, which inhibits the release of neurotransmitter at the photoreceptor synapse. Regulatory mechanisms are discussed in text.

Modified from Koutalos and Yau and used with permission


Figure 7.

Topology of mammalian adenylyl cyclase. Two homologous cytoplasmic domains (thick lines) are flanked by two membrane‐spanning domains containing six putative α‐helices each.



Figure 8.

Crosstalk in receptor coupling to adenylyl cyclase isoforms.

Modified from Pieroni et al. and used with permission


Figure 9.

Preferential substrate for family of phospholipases is phosphoglyceride with either ethanolamine, choline, or inositol group in R position.



Figure 10.

Stimulation of many transmembrane receptors leads to activation of phospholipases. Many important second messengers are generated from action of these phospholipases, including AA = arachadonic acid, InsP3 = inositol‐1,4,5‐trisphosphate, and DAG = diacylglycerol.



Figure 11.

Structural alignment of members of PLC (phospholipase C) subfamilies. X and Y denote critical catalytic domains found within all PLC isoforms. SH2 and SH3 domains, located in PLC‐γ isoforms, interact with activated tyrosine‐kinase‐linked receptors and effector molecules, respectively. EF‐hand is a putative Ca2+‐binding motif located exclusively in PLC‐δ isoforms.



Figure 12.

IKACh in inside‐out patches from atrial myocyes is activated by Gβγ and GTPγS. GTPγS activation of IKACh occurring by activation of endogenous G proteins, completely inhibited by purified Gα‐GDP, either bovine brain Gα or recombinant Gα13.IKACh is restimulated by a molar excess of Gβγ (from bovine brain or recombinant Gβ2γ5).



Figure 13.

Schematic depiction of families of RTKs.



Figure 14.

General scheme of signal transduction by RTKs. Ligand binding leads to RTK dimerization, which activates RTK tyrosine kinase and leads to autophosphorylation. Binding of SH2 domains of intracellular proteins to specific receptor phosphotyrosine residues mediates signaling through ligand‐bound receptor.



Figure 15.

SH2‐ and SH3‐containing proteins. SH2 domains are depicted in linear amino acid sequence as black box. SH3 domains are depicted by boxes labeled “3.” PTPase = protein tyrosine phosphatase, PLC = phospholipase C, GAP = GTPase‐activating protein, PI3K = phosphatidylinositol‐3‐OH kinase, and DBL = Dbl homology.

Modified from Pawson and Gish and used with permission


Figure 16.

SH2‐containing proteins bind to specific phosphotyrosine residues of activated PDGF receptor.

Modified from Pawson and Schlessinger and used with permission


Figure 17.

Ras cycle. GAP (GTPase‐activating proteins) and GDS (GDP‐dissociating stimulators) catalyze activation and inactivation of ras, respectively.



Figure 18.

Different RTKs use different methods to stimulate ras. After binding ligand (not shown), RTK phosphorylate specific tyrosines on themselves or other proteins. These phosphotyrosines form binding sites for SH2 domains of proteins that can recruit GRB‐2/SOS.



Figure 19.

RTK signaling pathways in different organisms.



Figure 20.

Mitogen‐activated protein kinase (MAPK) pathway. Catalytically active proteins are shown in ovals; inactive forms are shown in rectangles. (Described in the section Ras Stimulates the MAPK Pathway Via Its Effector, Raf‐1)



Figure 21.

Aspects of RTK signaling paradigm are used by other families of receptors.



Figure 22.

Regulation of MAPK pathway by G protein–coupled receptors.



Figure 23.

Pheromone receptor stimulation of MAPK in yeast. Three possible pathways are shown, supported by genetic analysis of S. cerevisiae.

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Kevin Wickman, Karen E. Hedin, Carmen M. Perez‐Terzic, Grigory B. Krapivinsky, Lisa Stehno‐Bittel, Bratislav Velimirovic, David E. Clapham. Mechanisms of Transmembrane Signaling. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 689-742. First published in print 1997. doi: 10.1002/cphy.cp140118