Regulation, Signaling, and Physiological Functions of G-Proteins

Journal of Molecular Biology

Volumn 428, Issue 19, 2016, Pages 3850-3868

  Syrovatkina, Viktoriya ^a   Alegre, Kamela O ^a   Dey, Raja ^a   Huang, Xin Yun ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

cellular signaling; G protein; GPCR

Indexed keywords

DIMER; G PROTEIN COUPLED RECEPTOR; GBA MOTIF CONTAINING PROTEIN; GLUCOSE REGULATED PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN; OLIGOMER; PROTEIN TYROSINE KINASE; REGULATOR PROTEIN; RGS PROTEIN; RIC 8 PROTEIN; UNCLASSIFIED DRUG;

CELL DIVISION; GENE INACTIVATION; HUMAN; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN INDUCTION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; BIOLOGICAL MODEL; CHEMISTRY; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MOLECULAR MODEL; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION;

ANIMALS; GENE EXPRESSION REGULATION; GTP-BINDING PROTEINS; HUMANS; MODELS, BIOLOGICAL; MODELS, MOLECULAR; PROTEIN CONFORMATION; PROTEIN MULTIMERIZATION; SIGNAL TRANSDUCTION;

EID: 84986888993     PISSN: 00222836     EISSN: 10898638     Source Type: Journal    
DOI: 10.1016/j.jmb.2016.08.002     Document Type: Review

References (154)

1. [1] Rosenbaum, D.M., Rasmussen, S.G., Kobilka, B.K., The structure and function of G-protein-coupled receptors. Nature. 459 (2009), 356–363.
2. [2] Pierce, K.L., Premont, R.T., Lefkowitz, R.J., Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3 (2002), 639–650.
3. [3] Gilman, A.G., G proteins: transducers of receptor-generated signals. Annu. Rev. Biochem. 56 (1987), 615–649.
4. [4] Bourne, H.R., Sanders, D.A., McCormick, F., The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 348 (1990), 125–132.
5. [5] Simon, M.I., Strathmann, M.P., Gautam, N., Diversity of G proteins in signal transduction. Science. 252 (1991), 802–808.
6. [6] Sprang, S.R., Chen, Z., Du, X., Structural basis of effector regulation and signal termination in heterotrimeric Galpha proteins. Adv. Protein Chem. 74 (2007), 1–65.
7. [7] Noel, J.P., Hamm, H.E., Sigler, P.B., The 2.2 A crystal structure of transducin-alpha complexed with GTP gamma S. Nature 366 (1993), 654–663.
8. [8] Coleman, D.E., Berghuis, A.M., Lee, E., Linder, M.E., Gilman, A.G., Sprang, S.R., Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science. 265 (1994), 1405–1412.
9. [9] Iiri, T., Farfel, Z., Bourne, H.R., G-protein diseases furnish a model for the turn-on switch. Nature. 394 (1998), 35–38.
10. [10] Cherfils, J., Chabre, M., Activation of G-protein Galpha subunits by receptors through Galpha–Gbeta and Galpha–Ggamma interactions. Trends Biochem. Sci. 28 (2003), 13–17.
11. [11] Tesmer, J.J., The quest to understand heterotrimeric G protein signaling. Nat. Struct. Mol. Biol. 17 (2010), 650–652.
12. [12] Choe, H.W., Park, J.H., Kim, Y.J., Ernst, O.P., Transmembrane signaling by GPCRs: insight from rhodopsin and opsin structures. Neuropharmacology. 60 (2011), 52–57.
13. [13] Katritch, V., Cherezov, V., Stevens, R.C., Structure–function of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53 (2013), 531–556.
14. [14] Huang, J., Chen, S., Zhang, J.J., Huang, X.Y., Crystal structure of oligomeric beta1-adrenergic G protein-coupled receptors in ligand-free basal state. Nat. Struct. Mol. Biol. 20 (2013), 419–425.
15. [15] Rasmussen, S.G., DeVree, B.T., Zou, Y., Kruse, A.C., Chung, K.Y., Kobilka, T.S., et al. Crystal structure of the beta2 adrenergic receptor–Gs protein complex. Nature. 477 (2011), 549–555.
16. [16] Ramachandran, S., Cerione, R.A., How GPCRs hit the switch. Nat. Struct. Mol. Biol. 13 (2006), 756–757.
17. [17] Schwartz, T.W., Sakmar, T.P., Structural biology: snapshot of a signalling complex. Nature. 477 (2011), 540–541.
18. [18] Oldham, W.M., Hamm, H.E., Heterotrimeric G protein activation by G-protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 9 (2008), 60–71.
19. [19] Lappano, R., Maggiolini, M., GPCRs and cancer. Acta Pharmacol. Sin. 33 (2012), 351–362.
20. [20] Sprang, S.R., G protein mechanisms: insights from structural analysis. Annu. Rev. Biochem. 66 (1997), 639–678.
21. [21] Wolf, Y.I., Brenner, S.E., Bash, P.A., Koonin, E.V., Distribution of protein folds in the three superkingdoms of life. Genome Res. 9 (1999), 17–26.
22. [22] Vetter, I.R., Wittinghofer, A., The guanine nucleotide-binding switch in three dimensions. Science. 294 (2001), 1299–1304.
23. [23] Rajagopal, K., Lefkowitz, R.J., Rockman, H.A., When 7 transmembrane receptors are not G protein-coupled receptors. J. Clin. Invest. 115 (2005), 2971–2974.
24. [24] Szczepek, M., Beyriere, F., Hofmann, K.P., Elgeti, M., Kazmin, R., Rose, A., et al. Crystal structure of a common GPCR-binding interface for G protein and arrestin. Nat. Commun., 5, 2014, 4801.
25. [25] Wess, J., G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J. 11 (1997), 346–354.
26. [26] Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C.G., Schertler, G.F., Babu, M.M., Molecular signatures of G-protein-coupled receptors. Nature. 494 (2013), 185–194.
27. [27] Strange, P.G., Signaling mechanisms of GPCR ligands. Curr. Opin. Drug Discov. Dev. 11 (2008), 196–202.
28. [28] Neubig, R.R., Gantzos, R.D., Thomsen, W.J., Mechanism of agonist and antagonist binding to alpha 2 adrenergic receptors: evidence for a precoupled receptor-guanine nucleotide protein complex. Biochemistry. 27 (1988), 2374–2384.
29. [29] Huang, J., Sun, Y., Zhang, J.J., Huang, X.Y., Pivotal role of extended linker 2 in the activation of Galpha by G protein-coupled receptor. J. Biol. Chem. 290 (2015), 272–283.
30. [30] Bouvier, M., Oligomerization of G-protein-coupled transmitter receptors. Nat. Rev. Neurosci. 2 (2001), 274–286.
31. [31] Angers, S., Salahpour, A., Bouvier, M., Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu. Rev. Pharmacol. Toxicol. 42 (2002), 409–435.
32. [32] Filizola, M., Weinstein, H., The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics. FEBS J. 272 (2005), 2926–2938.
33. [33] Milligan, G., The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. Curr. Opin. Pharmacol. 10 (2010), 23–29.
34. [34] Palczewski, K., Oligomeric forms of G protein-coupled receptors (GPCRs). Trends Biochem. Sci. 35 (2010), 595–600.
35. [35] Lohse, M.J., Dimerization in GPCR mobility and signaling. Curr. Opin. Pharmacol. 10 (2010), 53–58.
36. [36] Salom, D., Lodowski, D.T., Stenkamp, R.E., Le Trong, I., Golczak, M., Jastrzebska, B., et al. Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 16,123–16,128.
37. [37] Park, J.H., Scheerer, P., Hofmann, K.P., Choe, H.W., Ernst, O.P., Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 454 (2008), 183–187.
38. [38] Scheerer, P., Park, J.H., Hildebrand, P.W., Kim, Y.J., Krauss, N., Choe, H.W., et al. Crystal structure of opsin in its G-protein-interacting conformation. Nature. 455 (2008), 497–502.
39. [39] Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G.W., Vardy, E., et al. Structure of the human kappa-opioid receptor in complex with JDTic. Nature. 485 (2012), 327–332.
40. [40] Manglik, A., Kruse, A.C., Kobilka, T.S., Thian, F.S., Mathiesen, J.M., Sunahara, R.K., et al. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature. 485 (2012), 321–326.
41. [41] Wu, B., Chien, E.Y., Mol, C.D., Fenalti, G., Liu, W., Katritch, V., et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science. 330 (2010), 1066–1071.
42. [42] Mancia, F., Assur, Z., Herman, A.G., Siegel, R., Hendrickson, W.A., Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep. 9 (2008), 363–369.
43. [43] Guo, W., Urizar, E., Kralikova, M., Mobarec, J.C., Shi, L., Filizola, M., et al. Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J. 27 (2008), 2293–2304.
44. [44] Guo, W., Shi, L., Filizola, M., Weinstein, H., Javitch, J.A., Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 17,495–17,500.
45. [45] Sato, M., Ribas, C., Hildebrandt, J.D., Lanier, S.M., Characterization of a G-protein activator in the neuroblastoma-glioma cell hybrid NG108-15. J. Biol. Chem. 271 (1996), 30,052–30,060.
46. [46] Takesono, A., Cismowski, M.J., Ribas, C., Bernard, M., Chung, P., Hazard, S. 3rd, et al. Receptor-independent activators of heterotrimeric G-protein signaling pathways. J. Biol. Chem. 274 (1999), 33,202–33,205.
47. [47] Cismowski, M.J., Ma, C., Ribas, C., Xie, X., Spruyt, M., Lizano, J.S., et al. Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration. J. Biol. Chem. 275 (2000), 23,421–23,424.
48. [48] Bernard, M.L., Peterson, Y.K., Chung, P., Jourdan, J., Lanier, S.M., Selective interaction of AGS3 with G-proteins and the influence of AGS3 on the activation state of G-proteins. J. Biol. Chem. 276 (2001), 1585–1593.
49. [49] Kroslak, T., Koch, T., Kahl, E., Hollt, V., Human phosphatidylethanolamine-binding protein facilitates heterotrimeric G protein-dependent signaling. J. Biol. Chem. 276 (2001), 39,772–39,778.
50. [50] Miller, K.G., Emerson, M.D., McManus, J.R., Rand, J.B., RIC-8 (synembryn): a novel conserved protein that is required for G(q)alpha signaling in the C. elegans nervous system. Neuron 27 (2000), 289–299.
51. [51] Miller, K.G., Rand, J.B., A role for RIC-8 (synembryn) and GOA-1 (G(o)alpha) in regulating a subset of centrosome movements during early embryogenesis in Caenorhabditis elegans. Genetics. 156 (2000), 1649–1660.
52. [52] Hess, H.A., Roper, J.C., Grill, S.W., Koelle, M.R., RGS-7 completes a receptor-independent heterotrimeric G protein cycle to asymmetrically regulate mitotic spindle positioning in C. elegans. Cell. 119 (2004), 209–218.
53. [53] Afshar, K., Willard, F.S., Colombo, K., Johnston, C.A., McCudden, C.R., Siderovski, D.P., et al. RIC-8 is required for GPR-1/2-dependent galpha function during asymmetric division of C. elegans embryos. Cell 119 (2004), 219–230.
54. [54] Wang, H., Ng, K.H., Qian, H., Siderovski, D.P., Chia, W., Yu, F., Ric-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins. Nat. Cell Biol. 7 (2005), 1091–1098.
55. [55] Hampoelz, B., Hoeller, O., Bowman, S.K., Dunican, D., Knoblich, J.A., Drosophila Ric-8 is essential for plasma-membrane localization of heterotrimeric G proteins. Nat. Cell Biol. 7 (2005), 1099–1105.
56. [56] David, N.B., Martin, C.A., Segalen, M., Rosenfeld, F., Schweisguth, F., Bellaiche, Y., Drosophila Ric-8 regulates Galphai cortical localization to promote Galphai-dependent planar orientation of the mitotic spindle during asymmetric cell division. Nat. Cell Biol. 7 (2005), 1083–1090.
57. [57] Parks, S., Wieschaus, E., The Drosophila gastrulation gene concertina encodes a G alpha-like protein. Cell. 64 (1991), 447–458.
58. [58] Tall, G.G., Krumins, A.M., Gilman, A.G., Mammalian Ric-8A (synembryn) is a heterotrimeric galpha protein guanine nucleotide exchange factor. J. Biol. Chem. 278 (2003), 8356–8362.
59. [59] Tall, G.G., Gilman, A.G., Purification and functional analysis of Ric-8A: a guanine nucleotide exchange factor for G-protein alpha subunits. Methods Enzymol. 390 (2004), 377–388.
60. [60] Von Dannecker, L.E., Mercadante, A.F., Malnic, B., Ric-8B, an olfactory putative GTP exchange factor, amplifies signal transduction through the olfactory-specific G-protein Galphaolf. J. Neurosci. 25 (2005), 3793–3800.
61. [61] Tonissoo, T., Koks, S., Meier, R., Raud, S., Plaas, M., Vasar, E., et al. Heterozygous mice with Ric-8 mutation exhibit impaired spatial memory and decreased anxiety. Behav. Brain Res. 167 (2006), 42–48.
62. [62] Van Eps, N., Thomas, C.J., Hubbell, W.L., Sprang, S.R., The guanine nucleotide exchange factor Ric-8A induces domain separation and Ras domain plasticity in Galphai1. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 1404–1409.
63. [63] Chan, P., Gabay, M., Wright, F.A., Tall, G.G., Ric-8B is a GTP-dependent G protein alphas guanine nucleotide exchange factor. J. Biol. Chem. 286 (2011), 19,932–19,942.
64. [64] Gabay, M., Pinter, M.E., Wright, F.A., Chan, P., Murphy, A.J., Valenzuela, D.M., et al. Ric-8 proteins are molecular chaperones that direct nascent G protein alpha subunit membrane association. Sci. Signal., 4, 2011, ra79.
65. [65] Chan, P., Thomas, C.J., Sprang, S.R., Tall, G.G., Molecular chaperoning function of Ric-8 is to fold nascent heterotrimeric G protein alpha subunits. Proc. Natl. Acad. Sci. U. S. A. 110 (2013), 3794–3799.
66. [66] Afshar, K., Willard, F.S., Colombo, K., Siderovski, D.P., Gonczy, P., Cortical localization of the galpha protein GPA-16 requires RIC-8 function during C. elegans asymmetric cell division. Development. 132 (2005), 4449–4459.
67. [67] Mochizuki, N., Cho, G., Wen, B., Insel, P.A., Identification and cDNA cloning of a novel human mosaic protein, LGN, based on interaction with G alpha i2. Gene. 181 (1996), 39–43.
68. [68] Kimple, R.J., Kimple, M.E., Betts, L., Sondek, J., Siderovski, D.P., Structural determinants for GoLoco-induced inhibition of nucleotide release by Galpha subunits. Nature. 416 (2002), 878–881.
69. [69] Natochin, M., Lester, B., Peterson, Y.K., Bernard, M.L., Lanier, S.M., Artemyev, N.O., AGS3 inhibits GDP dissociation from galpha subunits of the Gi family and rhodopsin-dependent activation of transducin. J. Biol. Chem. 275 (2000), 40,981–40,985.
70. [70] Tall, G.G., Gilman, A.G., Resistance to inhibitors of cholinesterase 8A catalyzes release of Galphai-GTP and nuclear mitotic apparatus protein (NuMA) from NuMA/LGN/Galphai-GDP complexes. Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 16,584–16,589.
71. [71] Thomas, C.J., Tall, G.G., Adhikari, A., Sprang, S.R., Ric-8A catalyzes guanine nucleotide exchange on G alphai1 bound to the GPR/GoLoco exchange inhibitor AGS3. J. Biol. Chem. 283 (2008), 23,150–23,160.
72. [72] Cismowski, M.J., Takesono, A., Ma, C., Lizano, J.S., Xie, X., Fuernkranz, H., et al. Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signaling. Nat. Biotechnol. 17 (1999), 878–883.
73. [73] Yu, F., Morin, X., Cai, Y., Yang, X., Chia, W., Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization. Cell. 100 (2000), 399–409.
74. [74] Schaefer, M., Petronczki, M., Dorner, D., Forte, M., Knoblich, J.A., Heterotrimeric G proteins direct two modes of asymmetric cell division in the Drosophila nervous system. Cell. 107 (2001), 183–194.
75. [75] Gotta, M., Ahringer, J., Distinct roles for Galpha and Gbetagamma in regulating spindle position and orientation in Caenorhabditis elegans embryos. Nat. Cell Biol. 3 (2001), 297–300.
76. [76] Garcia-Marcos, M., Ghosh, P., Farquhar, M.G., GIV is a nonreceptor GEF for G alpha i with a unique motif that regulates Akt signaling. Proc. Natl. Acad. Sci. U. S. A. 106 (2009), 3178–3183.
77. [77] Garcia-Marcos, M., Ghosh, P., Farquhar, M.G., GIV/Girdin transmits signals from multiple receptors by triggering trimeric G protein activation. J. Biol. Chem. 290 (2015), 6697–6704.
78. [78] Le-Niculescu, H., Niesman, I., Fischer, T., DeVries, L., Farquhar, M.G., Identification and characterization of GIV, a novel Galpha i/s-interacting protein found on COPI, endoplasmic reticulum-Golgi transport vesicles. J. Biol. Chem. 280 (2005), 22,012–22,020.
79. [79] Ghosh, P., Garcia-Marcos, M., Farquhar, M.G., GIV/Girdin is a rheostat that fine-tunes growth factor signals during tumor progression. Cell Adhes. Migr. 5 (2011), 237–248.
80. [80] Barbazan, J., Dunkel, Y., Li, H., Nitsche, U., Janssen, K.P., Messer, K., et al. Prognostic impact of modulators of G proteins in circulating tumor cells from patients with metastatic colorectal cancer. Sci. Rep., 6, 2016, 22,112.
81. [81] Watson, N., Linder, M.E., Druey, K.M., Kehrl, J.H., Blumer, K.J., RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits. Nature. 383 (1996), 172–175.
82. [82] Soundararajan, M., Willard, F.S., Kimple, A.J., Turnbull, A.P., Ball, L.J., Schoch, G.A., et al. Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 6457–6462.
83. [83] Tesmer, J.J., Berman, D.M., Gilman, A.G., Sprang, S.R., Structure of RGS4 bound to AlF4-activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell. 89 (1997), 251–261.
84. [84] Baltoumas, F.A., Theodoropoulou, M.C., Hamodrakas, S.J., Interactions of the alpha-subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: a critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials. J. Struct. Biol. 182 (2013), 209–218.
85. [85] Sjogren, B., Regulator of G protein signaling proteins as drug targets: current state and future possibilities. Adv. Pharmacol. 62 (2011), 315–347.
86. [86] Wettschureck, N., Offermanns, S., Mammalian G proteins and their cell type specific functions. Physiol. Rev. 85 (2005), 1159–1204.
87. [87] Rhee, S.G., Bae, Y.S., Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem. 272 (1997), 15,045–15,048.
88. [88] Kozasa, T., Jiang, X., Hart, M.J., Sternweis, P.M., Singer, W.D., Gilman, A.G., et al. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13 [see comments]. Science. 280 (1998), 2109–2111.
89. [89] Lowry, W.E., Huang, J., Ma, Y.C., Ali, S., Wang, D., Williams, D.M., et al. Csk, a critical link of g protein signals to actin cytoskeletal reorganization. Dev. Cell. 2 (2002), 733–744.
90. [90] Lutz, S., Freichel-Blomquist, A., Yang, Y., Rumenapp, U., Jakobs, K.H., Schmidt, M., et al. The guanine nucleotide exchange factor p63RhoGEF, a specific link between Gq/11-coupled receptor signaling and RhoA. J. Biol. Chem. 280 (2005), 11,134–11,139.
91. [91] Worzfeld, T., Wettschureck, N., Offermanns, S., G(12)/G(13)-mediated signalling in mammalian physiology and disease. Trends Pharmacol. Sci. 29 (2008), 582–589.
92. [92] Jiang, Y., Ma, W., Wan, Y., Kozasa, T., Hattori, S., Huang, X.Y., The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature. 395 (1998), 808–813.
93. [93] Meigs, T.E., Fields, T.A., McKee, D.D., Casey, P.J., Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta-catenin release. Proc. Natl. Acad. Sci. U. S. A. 98 (2001), 519–524.
94. [94] Dhanasekaran, N., Dermott, J.M., Signaling by the G12 class of G proteins. Cell. Signal. 8 (1996), 235–245.
95. [95] Suzuki, N., Nakamura, S., Mano, H., Kozasa, T., Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc. Natl. Acad. Sci. U. S. A. 100 (2003), 733–738.
96. [96] Cvejic, S., Jiang, Y., Huang, X., Signaling of G(alpha)(12) family of G proteins through a tyrosine kinase and a Ras-GAP. Trends Cardiovasc. Med. 10 (2000), 160–165.
97. [97] Huang, W., Morales, J.L., Gazivoda, V.P., Lai, J., Qi, Q., August, A., The zinc-binding region of IL-2 inducible T cell kinase (Itk) is required for interaction with Galpha13 and activation of serum response factor. Int. J. Biochem. Cell Biol. 45 (2013), 1074–1082.
98. [98] Vaiskunaite, R., Adarichev, V., Furthmayr, H., Kozasa, T., Gudkov, A., Voyno-Yasenetskaya, T.A., Conformational activation of radixin by G13 protein alpha subunit. J. Biol. Chem. 275 (2000), 26,206–26,212.
99. [99] Radhika, V., Onesime, D., Ha, J.H., Dhanasekaran, N., Galpha13 stimulates cell migration through cortactin-interacting protein Hax-1. J. Biol. Chem. 279 (2004), 49,406–49,413.
100. [100] Gong, H., Shen, B., Flevaris, P., Chow, C., Lam, S.C., Voyno-Yasenetskaya, T.A., et al. G protein subunit Galpha13 binds to integrin alphaIIbbeta3 and mediates integrin “outside-in” signaling. Science. 327 (2010), 340–343.
101. [101] Khan, S.M., Sleno, R., Gora, S., Zylbergold, P., Laverdure, J.P., Labbe, J.C., et al. The expanding roles of Gbetagamma subunits in G protein-coupled receptor signaling and drug action. Pharmacol. Rev. 65 (2013), 545–577.
102. [102] Lohse, M.J., Engelhardt, S., Eschenhagen, T., What is the role of beta-adrenergic signaling in heart failure?. Circ. Res. 93 (2003), 896–906.
103. [103] Yu, S., Gavrilova, O., Chen, H., Lee, R., Liu, J., Pacak, K., et al. Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J. Clin. Invest. 105 (2000), 615–623.
104. [104] Yu, S., Yu, D., Lee, E., Eckhaus, M., Lee, R., Corria, Z., et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), 8715–8720.
105. [105] Yu, S., Castle, A., Chen, M., Lee, R., Takeda, K., Weinstein, L.S., Increased insulin sensitivity in Gsalpha knockout mice. J. Biol. Chem. 276 (2001), 19,994–19,998.
106. [106] Jiang, M., Spicher, K., Boulay, G., Wang, Y., Birnbaumer, L., Most central nervous system D2 dopamine receptors are coupled to their effectors by Go. Proc. Natl. Acad. Sci. U. S. A. 98 (2001), 3577–3582.
107. [107] Rudolph, U., Spicher, K., Birnbaumer, L., Adenylyl cyclase inhibition and altered G protein subunit expression and ADP-ribosylation patterns in tissues and cells from Gi2 alpha −/− mice. Proc. Natl. Acad. Sci. U. S. A. 93 (1996), 3209–3214.
108. [108] Gohla, A., Klement, K., Piekorz, R.P., Pexa, K., vom Dahl, S., Spicher, K., et al. An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 3003–3008.
109. [109] Williams, S.L., Lutz, S., Charlie, N.K., Vettel, C., Ailion, M., Coco, C., et al. Trio's Rho-specific GEF domain is the missing Galpha q effector in C. elegans. Genes Dev. 21 (2007), 2731–2746.
110. [110] Steven, R., Zhang, L., Culotti, J., Pawson, T., The UNC-73/Trio RhoGEF-2 domain is required in separate isoforms for the regulation of pharynx pumping and normal neurotransmission in C. elegans. Genes Dev. 19 (2005), 2016–2029.
111. [111] Offermanns, S., Mancino, V., Revel, J.P., Simon, M.I., Vascular system defects and impaired cell chemokinesis as a result of Galpha13 deficiency. Science. 275 (1997), 533–536.
112. [112] Gu, J.L., Muller, S., Mancino, V., Offermanns, S., Simon, M.I., Interaction of G alpha(12) with G alpha(13) and G alpha(q) signaling pathways. Proc. Natl. Acad. Sci. U. S. A. 99 (2002), 9352–9357.
113. [113] Ruppel, K.M., Willison, D., Kataoka, H., Wang, A., Zheng, Y.W., Cornelissen, I., et al. Essential role for Galpha13 in endothelial cells during embryonic development. Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 8281–8286.
114. [114] Moers, A., Nieswandt, B., Massberg, S., Wettschureck, N., Gruner, S., Konrad, I., et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat. Med. 9 (2003), 1418–1422.
115. [115] Manning, D.R., Evidence mounts for receptor-independent activation of heterotrimeric G proteins normally in vivo: positioning of the mitotic spindle in C. elegans. Sci. STKE, 2003, 2003, pe35.
116. [116] Zwaal, R.R., Ahringer, J., van Luenen, H.G., Rushforth, A., Anderson, P., Plasterk, R.H., G proteins are required for spatial orientation of early cell cleavages in C. elegans embryos. Cell 86 (1996), 619–629.
117. [117] Srinivasan, D.G., Fisk, R.M., Xu, H., van den Heuvel, S., A complex of LIN-5 and GPR proteins regulates G protein signaling and spindle function in C. elegans. Genes Dev. 17 (2003), 1225–1239.
118. [118] Colombo, K., Grill, S.W., Kimple, R.J., Willard, F.S., Siderovski, D.P., Gonczy, P., Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos. Science. 300 (2003), 1957–1961.
119. [119] Gotta, M., Dong, Y., Peterson, Y.K., Lanier, S.M., Ahringer, J., Asymmetrically distributed C. elegans homologs of AGS3/PINS control spindle position in the early embryo. Curr. Biol. 13 (2003), 1029–1037.
120. [120] Siller, K.H., Doe, C.Q., Spindle orientation during asymmetric cell division. Nat. Cell Biol. 11 (2009), 365–374.
121. [121] Couwenbergs, C., Labbe, J.C., Goulding, M., Marty, T., Bowerman, B., Gotta, M., Heterotrimeric G protein signaling functions with dynein to promote spindle positioning in C. elegans. J. Cell Biol. 179 (2007), 15–22.
122. [122] Couwenbergs, C., Spilker, A.C., Gotta, M., Control of embryonic spindle positioning and Galpha activity by C. elegans RIC-8. Curr. Biol. 14 (2004), 1871–1876.
123. [123] Woodard, G.E., Huang, N.N., Cho, H., Miki, T., Tall, G.G., Kehrl, J.H., Ric-8A and Gi alpha recruit LGN, NuMA, and dynein to the cell cortex to help orient the mitotic spindle. Mol. Cell. Biol. 30 (2010), 3519–3530.
124. [124] Waters, C., Sambi, B., Kong, K.C., Thompson, D., Pitson, S.M., Pyne, S., et al. Sphingosine 1-phosphate and platelet-derived growth factor (PDGF) act via PDGF beta receptor-sphingosine 1-phosphate receptor complexes in airway smooth muscle cells. J. Biol. Chem. 278 (2003), 6282–6290.
125. [125] Waters, C., Pyne, S., Pyne, N.J., The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin. Cell Dev. Biol. 15 (2004), 309–323.
126. [126] Daub, H., Weiss, F.U., Wallasch, C., Ullrich, A., Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 379 (1996), 557–560.
127. [127] Prenzel, N., Zwick, E., Daub, H., Leserer, M., Abraham, R., Wallasch, C., et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 402 (1999), 884–888.
128. [128] Moxham, C.M., Malbon, C.C., Insulin action impaired by deficiency of the G-protein subunit G ialpha2. Nature. 379 (1996), 840–844.
129. [129] Hobson, J.P., Rosenfeldt, H.M., Barak, L.S., Olivera, A., Poulton, S., Caron, M.G., et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science. 291 (2001), 1800–1803.
130. [130] Kluk, M.J., Colmont, C., Wu, M.T., Hla, T., Platelet-derived growth factor (PDGF)-induced chemotaxis does not require the G protein-coupled receptor S1P1 in murine embryonic fibroblasts and vascular smooth muscle cells. FEBS Lett. 533 (2003), 25–28.
131. [131] Alderton, F., Rakhit, S., Kong, K.C., Palmer, T., Sambi, B., Pyne, S., et al. Tethering of the platelet-derived growth factor beta receptor to G-protein-coupled receptors. A novel platform for integrative signaling by these receptor classes in mammalian cells. J. Biol. Chem. 276 (2001), 28,578–28,585.
132. [132] Sun, H., Chen, Z., Poppleton, H., Scholich, K., Mullenix, J., Weipz, G.J., et al. The juxtamembrane, cytosolic region of the epidermal growth factor receptor is involved in association with alpha-subunit of Gs. J. Biol. Chem. 272 (1997), 5413–5420.
133. [133] Pyne, N.J., Pyne, S., Receptor tyrosine kinase-G-protein-coupled receptor signalling platforms: out of the shadow?. Trends Pharmacol. Sci. 32 (2011), 443–450.
134. [134] Alberelli, M.A., De Candia, E., Functional role of protease activated receptors in vascular biology. Vasc. Pharmacol. 62 (2014), 72–81.
135. [135] Marty, C., Ye, R.D., Heterotrimeric G protein signaling outside the realm of seven transmembrane domain receptors. Mol. Pharmacol. 78 (2010), 12–18.
136. [136] Aznar, N., Kalogriopoulos, N., Midde, K.K., Ghosh, P., Heterotrimeric G protein signaling via GIV/Girdin: breaking the rules of engagement, space, and time. BioEssays 38 (2016), 379–393.
137. [137] Mellstroom, K., Hoglund, A.S., Nister, M., Heldin, C.H., Westermark, B., Lindberg, U., The effect of platelet-derived growth factor on morphology and motility of human glial cells. J. Muscle Res. Cell Motil. 4 (1983), 589–609.
138. [138] Schliwa, M., Nakamura, T., Porter, K.R., Euteneuer, U., A tumor promoter induces rapid and coordinated reorganization of actin and vinculin in cultured cells. J. Cell Biol. 99 (1984), 1045–1059.
139. [139] Mellstrom, K., Heldin, C.H., Westermark, B., Induction of circular membrane ruffling on human fibroblasts by platelet-derived growth factor. Exp. Cell Res. 177 (1988), 347–359.
140. [140] Warn, R., Brown, D., Dowrick, P., Prescott, A., Warn, A., Cytoskeletal changes associated with cell motility. Symp. Soc. Exp. Biol. 47 (1993), 325–338.
141. [141] Dowrick, P., Kenworthy, P., McCann, B., Warn, R., Circular ruffle formation and closure lead to macropinocytosis in hepatocyte growth factor/scatter factor-treated cells. Eur. J. Cell Biol. 61 (1993), 44–53.
142. [142] Suetsugu, S., Yamazaki, D., Kurisu, S., Takenawa, T., Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration. Dev. Cell. 5 (2003), 595–609.
143. [143] Bretscher, M.S., Getting membrane flow and the cytoskeleton to cooperate in moving cells. Cell. 87 (1996), 601–606.
144. [144] Krueger, E.W., Orth, J.D., Cao, H., McNiven, M.A., A dynamin–cortactin–Arp2/3 complex mediates actin reorganization in growth factor-stimulated cells. Mol. Biol. Cell 14 (2003), 1085–1096.
145. [145] Buccione, R., Orth, J.D., McNiven, M.A., Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat. Rev. Mol. Cell Biol. 5 (2004), 647–657.
146. [146] Blume-Jensen, P., Claesson-Welsh, L., Siegbahn, A., Zsebo, K.M., Westermark, B., Heldin, C.H., Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J. 10 (1991), 4121–4128.
147. [147] Ruthel, G., Banker, G., Role of moving growth cone-like “wave” structures in the outgrowth of cultured hippocampal axons and dendrites. J. Neurobiol. 39 (1999), 97–106.
148. [148] Hedberg, K.M., Bengtsson, T., Safiejko-Mroczka, B., Bell, P.B., Lindroth, M., PDGF and neomycin induce similar changes in the actin cytoskeleton in human fibroblasts. Cell Motil. Cytoskeleton. 24 (1993), 139–149.
149. [149] Dharmawardhane, S., Sanders, L.C., Martin, S.S., Daniels, R.H., Bokoch, G.M., Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. J. Cell Biol. 138 (1997), 1265–1278.
150. [150] Shan, D., Chen, L., Wang, D., Tan, Y.C., Gu, J.L., Huang, X.Y., The g protein galpha(13) is required for growth factor-induced cell migration. Dev. Cell. 10 (2006), 707–718.
151. [151] Wang, D., Tan, Y.C., Kreitzer, G.E., Nakai, Y., Shan, D., Zheng, Y., et al. G proteins G12 and G13 control the dynamic turnover of growth factor-induced dorsal ruffles. J. Biol. Chem. 281 (2006), 32,660–32,667.
152. [152] Wang, L., Guo, D., Xing, B., Zhang, J.J., Shu, H.B., Guo, L., et al. Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization. J. Biol. Chem. 286 (2011), 31,055–31,061.
153. [153] Xing, B., Wang, L., Guo, D., Huang, J., Espenel, C., Kreitzer, G., et al. Atypical protein kinase Clambda is critical for growth factor receptor-induced dorsal ruffle turnover and cell migration. J. Biol. Chem. 288 (2013), 32,827–32,836.
154. [154] Suzuki, A., Ohno, S., The PAR-aPKC system: lessons in polarity. J. Cell Sci. 119 (2006), 979–987.