g12 g13 gtp binding protein alpha subunits


Summary: A ubiquitously expressed family of heterotrimeric GTP-binding protein alpha subunits that signal through interactions with a variety of second messengers as GTPASE-ACTIVATING PROTEINS; GUANINE NUCLEOTIDE EXCHANGE FACTORS; and HEAT SHOCK PROTEINS. The G12-G13 part of the name is also spelled G12/G13.

Top Publications

  1. Moers A, Nieswandt B, Massberg S, Wettschureck N, Grüner S, Konrad I, et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med. 2003;9:1418-22 pubmed
    ..We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs. ..
  2. Riobo N, Manning D. Receptors coupled to heterotrimeric G proteins of the G12 family. Trends Pharmacol Sci. 2005;26:146-54 pubmed
  3. Lin F, Sepich D, Chen S, Topczewski J, Yin C, Solnica Krezel L, et al. Essential roles of G{alpha}12/13 signaling in distinct cell behaviors driving zebrafish convergence and extension gastrulation movements. J Cell Biol. 2005;169:777-87 pubmed
    ..These findings provide the first evidence that Galpha(12) and Galpha(13) have overlapping and essential roles in distinct cell behaviors that drive vertebrate gastrulation. ..
  4. Gu J, Muller S, Mancino V, Offermanns S, Simon M. Interaction of G alpha(12) with G alpha(13) and G alpha(q) signaling pathways. Proc Natl Acad Sci U S A. 2002;99:9352-7 pubmed
    ..These data indicate that the G alpha(12)-mediated signaling pathway functionally interacts not only with the G alpha(13)- but also with the G alpha(q/11)-mediated signaling systems. ..
  5. Girkontaite I, Missy K, Sakk V, Harenberg A, Tedford K, Pötzel T, et al. Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses. Nat Immunol. 2001;2:855-62 pubmed
    ..Although Lsc-deficient lymphocytes show reduced basal motility, MZB cells show enhanced migration after serum activation. Thus, Lsc is a critical regulator of MZB cells and immune functions. ..
  6. Vogt S, Grosse R, Schultz G, Offermanns S. Receptor-dependent RhoA activation in G12/G13-deficient cells: genetic evidence for an involvement of Gq/G11. J Biol Chem. 2003;278:28743-9 pubmed
    ..Our data clearly show that G12/G13 as well as Gq/G11 alone can couple GPCRs to the rapid activation of RhoA. Gq/G11-mediated RhoA activation occurs independently of phospholipase C-beta and appears to involve LARG. ..
  7. Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y. Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol Cell Biol. 2003;23:1534-45 pubmed
    ..These results indicate that integration of counteracting signals from the Gi- and the G12/13-Rho pathways directs either positive or negative regulation of Rac, and thus cell migration, upon activation of a single S1P receptor isoform. ..
  8. McLaughlin J, Shen L, Holinstat M, Brooks J, Dibenedetto E, Hamm H. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J Biol Chem. 2005;280:25048-59 pubmed
    ..This model provides an estimate that peptide activation alters receptor/G protein binding to favor Galpha(q) activation over Galpha(12/13) by approximately 800-fold. ..
  9. Booden M, Siderovski D, Der C. Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Mol Cell Biol. 2002;22:4053-61 pubmed
    ..Our findings suggest that the RhoA exchange factor LARG, unlike the related p115 RhoGEF and PDZ-RhoGEF proteins, can serve as an effector for Gq-coupled receptors, mediating their functional linkage to RhoA-dependent signaling pathways. ..

More Information


  1. Klages B, Brandt U, Simon M, Schultz G, Offermanns S. Activation of G12/G13 results in shape change and Rho/Rho-kinase-mediated myosin light chain phosphorylation in mouse platelets. J Cell Biol. 1999;144:745-54 pubmed
    ..We provide evidence that G12/G13-mediated Rho/Rho-kinase-dependent regulation of MLC phosphorylation participates in receptor-induced platelet shape change. ..
  2. Meigs T, Fedor Chaiken M, Kaplan D, Brackenbury R, Casey P. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002;277:24594-600 pubmed
  3. Gavard J, Gutkind J. Protein kinase C-related kinase and ROCK are required for thrombin-induced endothelial cell permeability downstream from Galpha12/13 and Galpha11/q. J Biol Chem. 2008;283:29888-96 pubmed publisher
    ..Ultimately, both pathways converge to cause cell-cell junction disruption and provoke vascular leakage. ..
  4. Hart M, Jiang X, Kozasa T, Roscoe W, Singer W, Gilman A, et al. Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Galpha13. Science. 1998;280:2112-4 pubmed
    ..In contrast, activated Galpha12 inhibited stimulation by Galpha13. Thus, p115 RhoGEF can directly link heterotrimeric G protein alpha subunits to regulation of Rho. ..
  5. Holinstat M, Mehta D, Kozasa T, Minshall R, Malik A. Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. J Biol Chem. 2003;278:28793-8 pubmed
    ..Thus, Rho activation in endothelial cells and the subsequent actin cytoskeletal re-arrangement require the cooperative interaction of both G12/13 and PKCalpha pathways that converge at p115RhoGEF. ..
  6. Meigs T, Fields T, McKee D, Casey P. 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. 2001;98:519-24 pubmed
  7. Lee Y, Malbon C, Wang H. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. J Biol Chem. 2004;279:54896-904 pubmed
    ..In a concerted effort, RhoA in tandem with Cdc42 and Rac1 activates the MEKK1/4, MEK1/MKK4, and JNK cascade, thereby stimulating formation of primitive endoderm. ..
  8. Manganello J, Huang J, Kozasa T, Voyno Yasenetskaya T, Le Breton G. Protein kinase A-mediated phosphorylation of the Galpha13 switch I region alters the Galphabetagamma13-G protein-coupled receptor complex and inhibits Rho activation. J Biol Chem. 2003;278:124-30 pubmed
    ..4). These results therefore suggest that PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203). ..
  9. Le Page S, Bi Y, Williams J. CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells. Am J Physiol Cell Physiol. 2003;285:C1197-206 pubmed
    ..These results show that in NIH3T3 cells bearing CCK-A receptors, CCK activates Rho primarily through G13, leading to rearrangement of the actin cytoskeleton. ..
  10. Kozasa T, Jiang X, Hart M, Sternweis P, Singer W, Gilman A, et al. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science. 1998;280:2109-11 pubmed
    ..This GEF may act as an intermediary in the regulation of Rho proteins by G13 and G12. ..
  11. Suzuki H, Motley E, Eguchi K, Hinoki A, Shirai H, Watts V, et al. Distinct roles of protease-activated receptors in signal transduction regulation of endothelial nitric oxide synthase. Hypertension. 2009;53:182-8 pubmed publisher
  12. Arai K, Maruyama Y, Nishida M, Tanabe S, Takagahara S, Kozasa T, et al. Differential requirement of G alpha12, G alpha13, G alphaq, and G beta gamma for endothelin-1-induced c-Jun NH2-terminal kinase and extracellular signal-regulated kinase activation. Mol Pharmacol. 2003;63:478-88 pubmed
    ..Thus, ERK was activated by G alpha(i)- and G beta gamma-dependent pathways. These results clearly demonstrate that differential pathways activate JNK and ERK. ..
  13. Bhattacharyya R, Banerjee J, Khalili K, Wedegaertner P. Differences in Galpha12- and Galpha13-mediated plasma membrane recruitment of p115-RhoGEF. Cell Signal. 2009;21:996-1006 pubmed publisher
    ..These studies provide new insight into the function and mechanisms of alpha(12/13)-mediated PM recruitment of p115-RhoGEF. ..
  14. Hu Y, Xing J, Chen L, Guo X, Du Y, Zhao C, et al. RGS22, a novel testis-specific regulator of G-protein signaling involved in human and mouse spermiogenesis along with GNA12/13 subunits. Biol Reprod. 2008;79:1021-9 pubmed publisher
    ..RGS22 may also play a role in GNA13 translocation from the cytoplasm to the nucleus during spermiogenesis. ..
  15. Stemmle L, Fields T, Casey P. The regulator of G protein signaling domain of axin selectively interacts with Galpha12 but not Galpha13. Mol Pharmacol. 2006;70:1461-8 pubmed
    ..These findings establish that the RGS domain of axin is able to directly interact with the alpha subunit of heterotrimeric G protein G12 and provide a unique tool to interdict Galpha12-mediated signaling processes. ..
  16. Kasai K, Takahashi M, Osumi N, Sinnarajah S, Takeo T, Ikeda H, et al. The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Genes Cells. 2004;9:49-58 pubmed
    ..The participation of RhoA, a pivotal molecular switch in many signal transduction pathways, may help explain how Shh can trigger a variety of cellular responses. ..
  17. Tobo A, Tobo M, Nakakura T, Ebara M, Tomura H, Mogi C, et al. Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton-Sensing GPR4 in Extracellular Acidification-Induced Responses. PLoS ONE. 2015;10:e0129334 pubmed publisher
  18. Kelley G, Reks S, Smrcka A. Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins. Biochem J. 2004;378:129-39 pubmed
    ..In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLCepsilon by distinct and overlapping pathways. ..
  19. Kelly P, Casey P, Meigs T. Biologic functions of the G12 subfamily of heterotrimeric g proteins: growth, migration, and metastasis. Biochemistry. 2007;46:6677-87 pubmed
    ..Further, we describe and discuss the expanding role of G12 proteins in the biology of cells, focusing on the distinct properties of this subfamily in regulating cell proliferation, cell migration, and metastatic invasion. ..
  20. Vaiskunaite R, Adarichev V, Furthmayr H, Kozasa T, Gudkov A, Voyno Yasenetskaya T. Conformational activation of radixin by G13 protein alpha subunit. J Biol Chem. 2000;275:26206-12 pubmed
    ..Our results identifying a new signaling pathway for Galpha(13) indicate that ERM proteins can be activated by and serve as effectors of heterotrimeric G proteins. ..
  21. Postma F, Jalink K, Hengeveld T, Offermanns S, Moolenaar W. Galpha(13) mediates activation of a depolarizing chloride current that accompanies RhoA activation in both neuronal and nonneuronal cells. Curr Biol. 2001;11:121-4 pubmed
    ..We further show that, in neuronal cells, this newly described Galpha(13) pathway may profoundly modulate membrane excitability during RhoA-regulated neurite remodeling. ..
  22. Jiang L, Collins J, Davis R, Fraser I, Sternweis P. Regulation of cAMP responses by the G12/13 pathway converges on adenylyl cyclase VII. J Biol Chem. 2008;283:23429-39 pubmed publisher
    ..Our results demonstrate that AC7 is a specific downstream effector of the G(12/13) pathway. ..
  23. Nieswandt B, Schulte V, Zywietz A, Gratacap M, Offermanns S. Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin alpha IIbbeta 3 activation in platelets. J Biol Chem. 2002;277:39493-8 pubmed
  24. Wu E, Tam B, Wong Y. Constitutively active alpha subunits of G(q/11) and G(12/13) families inhibit activation of the pro-survival Akt signaling cascade. FEBS J. 2006;273:2388-98 pubmed
    ..Collectively, this study demonstrated the inhibitory effect of activated G alpha11, G alpha14, G alpha16, G alpha12 and G alpha13 on pro-survival Akt signaling. ..
  25. Lauckner J, Jensen J, Chen H, Lu H, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105:2699-704 pubmed publisher
    ..GPR55 activation also inhibits M current. These results establish GPR55 as a cannabinoid receptor with signaling distinct from CB(1) and CB(2). ..
  26. Radhika V, Hee Ha J, Jayaraman M, Tsim S, Dhanasekaran N. Mitogenic signaling by lysophosphatidic acid (LPA) involves Galpha12. Oncogene. 2005;24:4597-603 pubmed
  27. Hu Y, Lu Y, Zhou Z, Du Y, Xing J, Wang L, et al. Defective expression of Galpha12 in the testes of azoospermia patients and in the spermatozoa with low motility. J Mol Med (Berl). 2006;84:416-24 pubmed
    ..Furthermore, Galpha12 may be a candidate protein responsible for azoospermia caused by spermatogenic disturbance or midpiece deformities. ..
  28. Rieken S, Herroeder S, Sassmann A, Wallenwein B, Moers A, Offermanns S, et al. Lysophospholipids control integrin-dependent adhesion in splenic B cells through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11). J Biol Chem. 2006;281:36985-92 pubmed
    ..Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11). ..
  29. 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. 2003;100:733-8 pubmed
    ..These results demonstrate the biochemical mechanism of Rho activation through Galpha12 and that the regulation of RhoGEFs by heterotrimeric G proteins G1213 is further modulated by tyrosine phosphorylation. ..
  30. Scott G, Leopardi S, Parker L, Babiarz L, Seiberg M, Han R. The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes. J Invest Dermatol. 2003;121:529-41 pubmed
    ..Because phagocytosis of melanosomes is recognized as an important mechanism for melanosome transfer to keratinocytes, these results suggest that Rho is a critical signaling intermediate in melanosome uptake in keratinocytes. ..
  31. Martin C, Mahon G, Klinger M, Kay R, Symons M, Der C, et al. The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene. 2001;20:1953-63 pubmed
    ..Taken together, these observations suggest that PAR-1 growth transformation is mediated, in part, by activation of RhoA. ..
  32. Yamaguchi Y, Katoh H, Mori K, Negishi M. Galpha(12) and Galpha(13) interact with Ser/Thr protein phosphatase type 5 and stimulate its phosphatase activity. Curr Biol. 2002;12:1353-8 pubmed
    ..5-fold. Moreover, we demonstrate that the active form of Galpha(12) translocates PP5 to the cell periphery and colocalizes with PP5. These results propose a new signaling pathway of G(12) family G proteins. ..
  33. Ponsioen B, van Zeijl L, Langeslag M, Berryman M, Littler D, Jalink K, et al. Spatiotemporal regulation of chloride intracellular channel protein CLIC4 by RhoA. Mol Biol Cell. 2009;20:4664-72 pubmed publisher
    ..We conclude that CLIC4 is regulated by RhoA to be targeted to the plasma membrane, where it may function not as an inducible chloride channel but rather by displaying Cys-dependent transferase activity toward a yet unknown substrate. ..
  34. Orth J, Lang S, Taniguchi M, Aktories K. Pasteurella multocida toxin-induced activation of RhoA is mediated via two families of G{alpha} proteins, G{alpha}q and G{alpha}12/13. J Biol Chem. 2005;280:36701-7 pubmed
    ..The data show that YM-254890 is able to block PMT activation of Galpha(q) and indicate that, in addition to Galpha(q), the Galpha(12/13) G proteins are targets of PMT. ..
  35. Neves S, Ram P, Iyengar R. G protein pathways. Science. 2002;296:1636-9 pubmed
    ..These cellular processes in turn regulate systemic functions such as embryonic development, gonadal development, learning and memory, and organismal homeostasis. ..
  36. Mayers C, Wadell J, McLean K, Venere M, Malik M, Shibata T, et al. The Rho guanine nucleotide exchange factor AKAP13 (BRX) is essential for cardiac development in mice. J Biol Chem. 2010;285:12344-54 pubmed publisher
    ..The results suggest that AKAP13 coordinates Galpha(12) and Rho signaling to an essential transcription program in developing cardiomyocytes. ..
  37. Rieken S, Sassmann A, Herroeder S, Wallenwein B, Moers A, Offermanns S, et al. G12/G13 family G proteins regulate marginal zone B cell maturation, migration, and polarization. J Immunol. 2006;177:2985-93 pubmed
    ..These data suggest that G12/G13 family G proteins contribute to the formation of the mature MZB cell compartment both by controlling MZB cell migration and by regulating MZB cell precursor maturation. ..
  38. Mao J, Wu D. Functional interaction of G alpha 13 with p115RhoGEF determined with transcriptional reporter system. Methods Enzymol. 2002;345:404-10 pubmed
  39. Suzuki H, Kimura K, Shirai H, Eguchi K, Higuchi S, Hinoki A, et al. Endothelial nitric oxide synthase inhibits G12/13 and rho-kinase activated by the angiotensin II type-1 receptor: implication in vascular migration. Arterioscler Thromb Vasc Biol. 2009;29:217-24 pubmed publisher
    ..The eNOS/NO cascade specifically targets the Rho/Rho-kinase system via inhibition of G(12/13) to prevent vascular migration induced by AngII, representing a novel signal cross-talk in cardiovascular protection by NO. ..
  40. Kilts J, Lin S, Lowe J, Kwatra M. Selective activation of human atrial Galpha12 and Galpha13 by Galphaq-coupled angiotensin and endothelin receptors. J Cardiovasc Pharmacol. 2007;50:299-303 pubmed
    ..These differences in the activation of Galpha12 and Galpha13 by Galphaq-coupled receptors may underlie reported differences in the functions of these receptors. ..
  41. Kutuzov M, Andreeva A, Voyno Yasenetskaya T. Regulation of apoptosis signal-regulating kinase 1 degradation by G alpha13. FASEB J. 2007;21:3727-36 pubmed
    ..Our findings indicate that ASK1 expression levels can be regulated by G alpha13, at least in part via control of ASK1 ubiquitination and degradation. ..
  42. Aminova L, Luo S, Bannai Y, Ho M, Wilson B. The C3 domain of Pasteurella multocida toxin is the minimal domain responsible for activation of Gq-dependent calcium and mitogenic signaling. Protein Sci. 2008;17:945-9 pubmed publisher
    ..Using this approach, we have defined the last 180 amino acids, which encompass the C3 domain in the crystal structure, as the minimum domain sufficient to activate both NFAT and SRE signaling pathways. ..
  43. Yao R, Lemon W, Wang Y, Grubbs C, Lubet R, You M. Altered gene expression profile in mouse bladder cancers induced by hydroxybutyl(butyl)nitrosamine. Neoplasia. 2004;6:569-77 pubmed
  44. Yamazaki J, Katoh H, Yamaguchi Y, Negishi M. Two G12 family G proteins, G alpha12 and G alpha13, show different subcellular localization. Biochem Biophys Res Commun. 2005;332:782-6 pubmed
    ..This different localization of G alpha12 and G alpha13 may explain some of the nonoverlapping actions of G alpha12 and G alpha13. ..
  45. Vazquez Prado J, Basile J, Gutkind J. Modular architecture and novel protein-protein interactions regulating the RGS-containing Rho guanine nucleotide exchange factors. Methods Enzymol. 2004;390:259-85 pubmed
    ..This article describes the experimental strategies that have been utilized to begin unraveling the molecular mechanisms regulating the functional activity of RGS-containing RhoGEFs. ..
  46. Xu H, Wang X, Partilla J, Bishop Mathis K, Benaderet T, Dersch C, et al. Differential effects of opioid agonists on G protein expression in CHO cells expressing cloned human opioid receptors. Brain Res Bull. 2008;77:49-54 pubmed publisher
  47. Firth T, Jones S. GTP-binding protein Gq mediates muscarinic-receptor-induced inhibition of the inwardly rectifying potassium channel IRK1 (Kir 2.1). Neuropharmacology. 2001;40:358-65 pubmed
    ..These findings suggest that the m1 muscarinic-receptor-induced inhibition of IRK1 is mediated by the heterotrimeric G-protein, Galpha(q), in tsA cells. ..
  48. Vanni C, Mancini P, Ottaviano C, Ognibene M, Parodi A, Merello E, et al. Galpha13 regulation of proto-Dbl signaling. Cell Cycle. 2007;6:2058-70 pubmed
    ..These results suggest a mechanism by which proto-Dbl and its effector pathways are regulated by Galpha(13)-mediated signals through association with ezrin. ..
  49. Yamazaki J, Katoh H, Negishi M. Lysophosphatidic acid and thrombin receptors require both G alpha12 and G alpha13 to regulate axonal morphology in hippocampal neurons. Biol Pharm Bull. 2008;31:2216-22 pubmed
    ..These results suggest that thrombin and LPA receptors couple to both G alpha(12) and G alpha(13) for growth cone collapse. ..
  50. Yamakaw K, Kitamura K, Nonoguchi H, Takasu N, Miller R, Tomita K. Galpha13 induces preproET-1 gene expression via JNK. Hypertens Res. 2002;25:427-32 pubmed
    ..Our results also suggest that this Galpha13-coupled signaling pathway may play an important role in a sustained ET-1 autoinduction loop in various pathophysiological conditions. ..
  51. Krawetz R, Kelly G. Coordinate Galpha13 and Wnt6-beta-catenin signaling in F9 embryonal carcinoma cells is required for primitive endoderm differentiation. Biochem Cell Biol. 2009;87:567-80 pubmed publisher
  52. Ziembicki J, Tandon R, Schelling J, Sedor J, Miller R, Huang C. Mechanical force-activated phospholipase D is mediated by Galpha12/13-Rho and calmodulin-dependent kinase in renal epithelial cells. Am J Physiol Renal Physiol. 2005;289:F826-34 pubmed
    ..The signaling pathways for PLD activation involve Galpha(12/13)/Rho/F-actin and calmodulin-dependent kinase. ..
  53. Johnson E, Seasholtz T, Waheed A, Kreutz B, Suzuki N, Kozasa T, et al. RGS16 inhibits signalling through the G alpha 13-Rho axis. Nat Cell Biol. 2003;5:1095-103 pubmed
    ..These results elucidate a new mechanism whereby a classical RGS protein regulates G alpha 13-mediated signal transduction independently of the RGS box. ..