RhoG was first identified as acoding sequence upregulated in hamster lungfibroblasts upon stimulation withserum.[7] Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts,[8]leukocytes,[9][10]neuronal cells,[11]endothelial cells[12] andHeLa cells.[13] RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates.[14] 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.[8][15]
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 asGuanine 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 asGTPase activating proteins (GAPs) and these promotehydrolysis of GTP to GDP (via the intrinsicGTPase activity of the G protein) thus terminating RhoG-mediated signalling. A third group, known asGuanine 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 thecytosol 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 GEFTRIO which is able to promote nucleotide exchange on RhoG and Rac[19] (via its GEFD1 domain) and also onRhoA[20] via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promoteNGF-induced neurite outgrowth inPC12 cells[21] andphagocytosis ofapoptotic cells inC. elegans.[22] Another GEF, known asSGEF (Src homology 3 domain-containingGuanine nucleotideExchangeFactor), is thought to be RhoG-specific and has been reported to stimulatemacropinocytosis (internalisation ofextracellular fluid) in fibroblasts[23] and apical cup assembly in endothelial cells (an important stage inleukocyte trans-endothelial migration).[12] Other GEFs reported to interact with RhoG include Dbs,ECT2,VAV2 andVAV3.[15][24][25]
There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples includeIQGAP2[15] andRhoGDI3.[26]
Activated G proteins are able to couple to multiple downstream effectors and can therefore control a number of distinct signalling pathways (a characteristic known aspleiotropy). 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 ofRac via the DOCK (dedicatorofcytokinesis)-family of GEFs.[27] 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 proteinELMO (engulfment and cellmotility)[28] which binds RhoG at itsN-terminus. The proposed model for RhoG-dependent Rac activation involves recruitment of the ELMO/Dock180 complex to activated RhoG at theplasma membrane and this relocalisation, together with an ELMO-dependent conformational change in Dock180, is sufficient to promote GTP-loading of Rac.[29][30] RhoG-mediated Rac signalling has been shown to promote neurite outgrowth[11] and cell migration[13] in mammalian cells as well as phagocytosis of apoptotic cells inC. elegans.[22]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Ridley AJ (October 2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking".Trends in Cell Biology.16 (10):522–9.doi:10.1016/j.tcb.2006.08.006.PMID16949823.
^Yamaki N, Negishi M, Katoh H (August 2007). "RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism".Experimental Cell Research.313 (13):2821–32.doi:10.1016/j.yexcr.2007.05.010.PMID17570359.
^Blangy A, Vignal E, Schmidt S, Debant A, Gauthier-Rouvière C, Fort P (February 2000). "TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG".Journal of Cell Science.113 (Pt 4):729–39.doi:10.1242/jcs.113.4.729.PMID10652265.
^Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS (August 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex".Nature Cell Biology.4 (8):574–82.doi:10.1038/ncb824.PMID12134158.S2CID36363774.
^Lu M, Kinchen JM, Rossman KL, Grimsley C, deBakker C, Brugnera E, Tosello-Trampont AC, Haney LB, Klingele D, Sondek J, Hengartner MO, Ravichandran KS (August 2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180".Nature Structural & Molecular Biology.11 (8):756–62.doi:10.1038/nsmb800.PMID15247908.S2CID125990.
^Neudauer CL, Joberty G, Macara IG (January 2001). "PIST: a novel PDZ/coiled-coil domain binding partner for the rho-family GTPase TC10".Biochemical and Biophysical Research Communications.280 (2):541–7.doi:10.1006/bbrc.2000.4160.PMID11162552.
Taviaux SA, Vincent S, Fort P, Demaille JG (June 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.PMID8325658.
Jankowski A, Zhu P, Marshall JG (September 2008). "Capture of an activated receptor complex from the surface of live cells by affinity receptor chromatography".Analytical Biochemistry.380 (2):235–48.doi:10.1016/j.ab.2008.05.047.PMID18601892.
Le Gallic L, Fort P (May 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.PMID9177787.
Hiramoto K, Negishi M, Katoh H (December 2006). "Dock4 is regulated by RhoG and promotes Rac-dependent cell migration".Experimental Cell Research.312 (20):4205–16.doi:10.1016/j.yexcr.2006.09.006.PMID17027967.
