RhoG

Ras homolog family member G
Identifiers
Symbols	RHOG ; ARHG
External IDs	OMIM: 179505 MGI: 1928370 HomoloGene: 68196 GeneCards: RHOG Gene
Gene ontology Molecular function • GTPase activity • protein binding • GTP binding Cellular component • endoplasmic reticulum membrane • cytosol • plasma membrane • focal adhesion • extracellular exosome Biological process • small GTPase mediated signal transduction • Rho protein signal transduction • axon guidance • blood coagulation • positive regulation of cell proliferation • Rac protein signal transduction • actin cytoskeleton organization • platelet activation • positive regulation of transcription, DNA-templated • regulation of small GTPase mediated signal transduction • cell chemotaxis • positive regulation of establishment of protein localization to plasma membrane • activation of GTPase activity • regulation of ruffle assembly Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	391	56212
Ensembl	ENSG00000177105	ENSMUSG00000073982
UniProt	P84095	P84096
RefSeq (mRNA)	NM_001665	NM_019566
RefSeq (protein)	NP_001656	NP_062512
Location (UCSC)	Chr 11: 3.83 – 3.84 Mb	Chr 7: 102.24 – 102.25 Mb
PubMed search

RhoG (Ras homology Growth-related) (or ARGH) is a small (~21 kDa) monomeric GTP-binding protein (G protein), and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins^[1] and is encoded by the gene RHOG.^[2]

Discovery

RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serum.^[3] Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts,^[4] leukocytes,^[5][6] neuronal cells,^[7] endothelial cells^[8] and HeLa cells.^[9] RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates.^[10] RhoG shares a subset of common binding partners with Rac, Cdc42 and RhoU/V members but a major specificity is its inability to bind to CRIB domain proteins such as PAKs.^[4][11]

Function

Like most small G proteins RhoG is involved in a diverse set of cellular signalling mechanisms. In mammalian cells these include cell motility (through regulation of the actin cytoskeleton),^[9] gene transcription,^[6][12] endocytosis,^[13] neurite outgrowth,^[7] protection from anoikis^[14] and regulation of the neutrophil NADPH oxidase.^[5]

Regulation of RhoG activity

As with all small G proteins RhoG is able to signal to downstream effectors when bound to GTP (Guanosine triphosphate) and unable to signal when bound to GDP (Guanosine diphosphate). Three classes of protein interact with RhoG to regulate GTP/GDP loading. The first are known as Guanine nucleotide exchange factors (GEFs) and these facilitate the exchange of GDP for GTP so as to promote subsequent RhoG-mediated signalling. The second class are known as GTPase activating proteins (GAPs) and these promote hydrolysis of GTP to GDP (via the intrinsic GTPase activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known as Guanine nucleotide dissociation inhibitors (GDIs), inhibit dissociation of GDP and thus lock the G protein in its inactive state. GDIs can also sequester G proteins in the cytosol which also prevents their activation. The dynamic regulation of G protein signalling is necessarily complex and the 130 or more GEFs, GAPs and GDIs described thus far for the Rho family are considered to be the primary determinants of their spatiotemporal activity.

There are a number of GEFs reported to interact with RhoG, although in some cases the physiological significance of these interactions has yet to be proven. Well characterised examples include the dual specificity GEF TRIO which is able to promote nucleotide exchange on RhoG and Rac^[15] (via its GEFD1 domain) and also on RhoA^[16] via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in PC12 cells^[17] and phagocytosis of apoptotic cells in C. elegans.^[18] Another GEF, known as SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor), is thought to be RhoG-specific and has been reported to stimulate macropinocytosis (internalisation of extracellular fluid) in fibroblasts^[19] and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration).^[8] Other GEFs reported to interact with RhoG include Dbs, ECT2, VAV2 and VAV3.^[11][20][21]

There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2^[11] and RhoGDI3.^[22]

Signalling downstream of RhoG

Activated G proteins are able to couple to multiple downstream effectors and can therefore control a number of distinct signalling pathways (a characteristic known as pleiotropy). The extent to which RhoG regulates these pathways is poorly understood thus far, however, one specific pathway downstream of RhoG has received much attention and is therefore well characterised. This pathway involves RhoG-dependent activation of Rac via the DOCK (dedicator of cytokinesis)-family of GEFs.^[23] This family is divided into four subfamilies (A-D) and it is subfamilies A and B that are involved in the pathway described here. Dock180, the archetypal member of this family, is seen as an atypical GEF in that efficient GEF activity requires the presence of the DOCK-binding protein ELMO (engulfment and cell motility)^[24] which binds RhoG at its N-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the ELMO/Dock180 complex to activated RhoG at the plasma membrane and this relocalisation, together with an ELMO-dependent conformational change in Dock180, is sufficient to promote GTP-loading of Rac.^[25][26] RhoG-mediated Rac signalling has been shown to promote neurite outgrowth^[7] and cell migration^[9] in mammalian cells as well as phagocytosis of apoptotic cells in C. elegans.^[18]

Other proteins known to bind RhoG in its GTP-bound state include the microtubule-associated protein kinectin,^[27] Phospholipase D1 and the MAP Kinase activator MLK3.^[11]

Interactions

RhoG has been shown to interact with KTN1.^[28][29]

References

1. Ridley AJ (October 2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends Cell Biol. 16 (10): 522–9. doi:10.1016/j.tcb.2006.08.006. PMID 16949823.
2. "Entrez Gene: RHOG ras homolog gene family, member G (rho G)".
3. Vincent S, Jeanteur P, Fort P (July 1992). "Growth-regulated expression of rhoG, a new member of the ras homolog gene family". Mol. Cell. Biol. 12 (7): 3138–48. PMC 364528. PMID 1620121.
4. Gauthier-Rouviere C, Vignal E, Meriane M, et al. (June 1998). "RhoG GTPase Controls a Pathway That Independently Activates Rac1 and Cdc42Hs". Mol. Biol. Cell 9 (6): 1379–94. doi:10.1091/mbc.9.6.1379. PMC 25357. PMID 9614181.
5. Condliffe AM, Webb LM, Ferguson GJ, et al. (May 2006). "RhoG regulates the neutrophil NADPH oxidase". J. Immunol. 176 (9): 5314–20. doi:10.4049/jimmunol.176.9.5314. PMID 16621998.
6. Vigorito E, Billadeu D, Savoy D, et al. (January 2003). "RhoG regulates gene expression and the actin cytoskeleton in lymphocytes". Oncogene 22 (3): 330–42. doi:10.1038/sj.onc.1206116. PMID 12545154.
7. Katoh H, Yasui H, Yamaguchi Y, et al. (October 2000). "Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells". Mol. Cell. Biol. 20 (19): 7378–87. doi:10.1128/MCB.20.19.7378-7387.2000. PMC 86291. PMID 10982854.
8. van Buul JD, Allingham MJ, Samson T, et al. (September 2007). "RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration". J. Cell Biol. 178 (7): 1279–93. doi:10.1083/jcb.200612053. PMC 2064659. PMID 17875742.
9. Katoh H, Hiramoto K, Negishi M (January 2006). "Activation of Rac1 by RhoG regulates cell migration". J. Cell. Sci. 119 (Pt 1): 56–65. doi:10.1242/jcs.02720. PMID 16339170.
10. Boureux A, Vignal E, Faure S, Fort P. (2007). "Variability and Expression of Ankyrin Domain Genes in Wolbachia Variants Infecting the Mosquito Culex pipiens". Mol Biol Evol 24 (1): 203–16. doi:10.1128/JB.00142-07. ISSN 0021-9193. PMC 1913362. PMID 17449622.
11. Wennerberg K, Ellerbroek SM, Liu RY, et al. (December 2002). "RhoG signals in parallel with Rac1 and Cdc42". J. Biol. Chem. 277 (49): 47810–7. doi:10.1074/jbc.M203816200. PMID 12376551.
12. Murga C, Zohar M, Teramoto H, Gutkind JS (January 2002). "Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-κB". Oncogene 21 (2): 207–16. doi:10.1038/sj.onc.1205036. PMID 11803464.
13. Prieto-Sanchez RM, Berenjeno IM, Bustelo XR (May 2006). "Involvement of the Rho/Rac family member RhoG in caveolar endocytosis". Oncogene 25 (21): 2961–73. doi:10.1038/sj.onc.1209333. PMC 1463992. PMID 16568096.
14. Yamaki N, Negishi M, Katoh H (August 2007). "RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism". Exp. Cell Res. 313 (13): 2821–32. doi:10.1016/j.yexcr.2007.05.010. PMID 17570359.
15. Blangy A, Vignal, E, Schmidt S; et al. (February 2000). "TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of RhoG". J. Cell Sci. 113 (Pt 4): 729–39. PMID 10652265.
16. Bellanger J, Lazaro J, Diriong S, et al. (January 1998). "The two guanine nucleotide exchange factor domains of Trio link the Rac1 and the RhoA pathways in vivo". Oncogene 16 (2): 147–52. doi:10.1038/sj.onc.1201532. PMID 9464532.
17. Estrach S, Schmidt S, Diriong S, et al. (February 2002). "The Human Rho-GEF trio and its downstream target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth". Curr. Biol. 12 (4): 307–12. doi:10.1016/S0960-9822(02)00658-9. PMID 11864571.
18. deBakker CD, Haney LB, Kinchen JM, et al. (December 2004). "Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO". Curr. Biol. 14 (24): 2208–16. doi:10.1016/j.cub.2004.12.029. PMID 15620647.
19. Ellerbroek SM, Wennerberg K, Arthur T, et al. (July 2004). "SGEF, a RhoG Guanine Nucleotide Exchange Factor that Stimulates Macropinocytosis". Mol. Biol. Cell 15 (7): 3309–19. doi:10.1091/mbc.E04-02-0146. PMC 452585. PMID 15133129.
20. Schuebel KE, Movilla N, Rosa JL, et al. (November 1998). "Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2". EMBO J. 17 (22): 6608–21. doi:10.1093/emboj/17.22.6608. PMC 1171007. PMID 9822605.
21. Movilla N and Bustelo XR (November 1999). "Biological and Regulatory Properties of Vav-3, a New Member of the Vav Family of Oncoproteins". Mol. Cell. Biol. 19 (11): 7870–85. PMC 84867. PMID 10523675.
22. Zalcman G, Closson V, Camonis J, et al. (November 1996). "RhoGDI-3 is a new GDP dissociation inhibitor (GDI). Identification of a non-cytosolic GDI protein interacting with the small GTP-binding proteins RhoB and RhoG". J. Biol. Chem. 271 (48): 30366–74. doi:10.1074/jbc.271.48.30366. PMID 8939998.
23. Cote J, Vuori K (August 2007). "GEF what? Dock180 and related proteins help Rac to polarize cells in new ways". Trends Cell Biol. 17 (8): 383–93. doi:10.1016/j.tcb.2007.05.001. PMC 2887429. PMID 17765544.
24. Brugnera E, Haney L, Grimsley C, et al. (August 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex". Nat. Cell Biol. 4 (8): 574–82. doi:10.1038/ncb824. PMID 12134158.
25. Lu M, Kinchen JM, Rossman KL, et al. (August 2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nat. Struct. Mol. Biol. 11 (8): 756–62. doi:10.1038/nsmb800. PMID 15247908.
26. Katoh H, Negishi M (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature 424 (6947): 461–64. doi:10.1038/nature01817. PMID 12879077.
27. Vignal E, Blangy A, Martin M, et al. (December 2001). "Kinectin Is a Key Effector of RhoG Microtubule-Dependent Cellular Activity". Mol. Cell. Biol. 21 (23): 8022–34. doi:10.1128/MCB.21.23.8022-8034.2001. PMC 99969. PMID 11689693.
28. Neudauer, C L; Joberty G; Macara I G (January 2001). "PIST: a novel PDZ/coiled-coil domain binding partner for the rho-family GTPase TC10". Biochem. Biophys. Res. Commun. (United States) 280 (2): 541–7. doi:10.1006/bbrc.2000.4160. ISSN 0006-291X. PMID 11162552.
29. Vignal, E; Blangy A; Martin M; Gauthier-Rouvière C; Fort P (Dec 2001). "Kinectin Is a Key Effector of RhoG Microtubule-Dependent Cellular Activity". Mol. Cell. Biol. (United States) 21 (23): 8022–34. doi:10.1128/MCB.21.23.8022-8034.2001. ISSN 0270-7306. PMC 99969. PMID 11689693.

Further reading

• Taviaux SA, Vincent S, Fort P, Demaille JG (1993). "Localization of ARHG, a member of the RAS homolog gene family, to 11p15.5-11p15.4 by fluorescence in situ hybridization". Genomics 16 (3): 788–90. doi:10.1006/geno.1993.1271. PMID 8325658.
• Prieto-Sanchez RM, Bustelo XR (2003). "Structural Basis for the Signalling Specificity of RhoG and Rac1 GTPases". J. Biol. Chem. 278 (39): 37916–25. doi:10.1074/jbc.M301437200. PMID 12805377.
• Patel JC, Galan JE (2008). "Investigating the Function of Rho Family GTPases during Salmonella/Host Cell Interactions". Meth. Enzym. Methods in Enzymology 439: 145–58. doi:10.1016/S0076-6879(07)00411-9. ISBN 978-0-12-374311-4. PMC 2677710. PMID 18374162.
• Patel JC, Galan JE (2006). "Differential activation and function of Rho GTPases during Salmonella–host cell interactions". J. Cell. Biol. 175 (3): 453–63. doi:10.1083/jcb.200605144. PMC 2064522. PMID 17074883.
• Meller N, Merlot S, Guda C (2005). "CZH proteins: a new family of Rho-GEFs". J. Cell. Sci. 118 (Pt 21): 4937–46. doi:10.1242/jcs.02671. PMID 16254241.
• Lu M, Kinchen JM, Rossman KL (2005). "A Steric-Inhibition Model for Regulation of Nucleotide Exhchange via the Dock180 Family of GEFs". Curr. Biol. 15 (4): 371–77. doi:10.1016/j.cub.2005.01.050. PMID 15723800.
• Jankowski A, Zhu P, Marshall JG (2008). "Capture of an activated complex from the surface of live cells by affinity receptor chromatography". Anal. Biochem. 380 (2): 235–48. doi:10.1016/j.ab.2008.05.047. PMID 18601892.
• Vigorito E, Bell S, Hebeis BJ, et al. (2004). "Immunological Function in Mice Lacking the Rac-Related GTPase RhoG". Mol. Cell. Biol. 24 (2): 719–29. doi:10.1128/MCB.24.2.719-729.2004. PMC 343784. PMID 14701744.
• Meller J, Vidali L, Schwartz MA (2008). "Endogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration". J. Cell. Sci 121 (Pt 12): 1981–89. doi:10.1242/jcs.025130. PMC 2759683. PMID 18505794.
• Miki T, Smith CL, Long JE, et al. (1993). "Oncogene ect2 is related to regulators of small GTP-binding proteins". Nature 362 (6419): 462–5. doi:10.1038/362462a0. PMID 8464478.
• Le Gallic L, Fort P (1997). "Structure of the human ARHG locus encoding the Rho/Rac-like RhoG GTPase". Genomics 42 (1): 157–60. doi:10.1006/geno.1997.4703. PMID 9177787.
• Booden MA, Campbell SL, Der CJ (2002). "Critical but Distinct Roles for the Pleckstrin Homology and Cysteine-Rich Domains as Positive Modulators of Vav2 Signaling and Transformation". Mol. Cell. Biol. 22 (8): 2487–97. doi:10.1128/MCB.22.8.2487-2497.2002. PMC 133724. PMID 11909943.
• Skowronek KR, Guo F, Zheng Y, Nassar N (2004). "The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids". J. Biol. Chem. 279 (36): 37895–907. doi:10.1074/jbc.M312677200. PMID 15199069.
• Hiramoto K, Negishi M, Katoh H (2007). "Dock4 is regulated by RhoG and promotes Rac-dependent cell migration". Exp. Cell Res. 312 (20): 4205–16. doi:10.1016/j.yexcr.2006.09.006. PMID 17027967.
• Gumienny TL, Brugnera E, Tosello-Trampont A, et al. (2001). "CED-12/ELMO, a Novel Member of the CrkII/Dock180/Rac Pathway, Is Required for Phagocytosis and Cell Migration". Cell 107 (1): 27–41. doi:10.1016/S0092-8674(01)00520-7. PMID 11595183.
• Kunisaki Y, Nishikimi A, Tanaka Y, et al. (2006). "DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis". J. Cell. Biol. 174 (5): 647–52. doi:10.1083/jcb.200602142. PMC 2064308. PMID 16943182.
• Lu M, Ravichandran KS (2006). "Dock180-ELMO Cooperation in Rac Activation". Meth. Enzym. 406: 388–402. doi:10.1016/S0076-6879(06)06028-9. PMID 16472672.