RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serum. Expression of RhoG in mammals is widespread and studies of its function have been carried out in fibroblasts,leukocytes,neuronal cells,endothelial cells and HeLa cells. RhoG belongs to the Rac subgroup and emerged as a consequence of retroposition in early vertebrates. 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.
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 (via its GEFD1 domain) and also on RhoA via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in PC12 cells and phagocytosis of apoptotic cells in C. elegans. 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 and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration). Other GEFs reported to interact with RhoG include Dbs, ECT2, VAV2 and VAV3.
There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2 and RhoGDI3.
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. 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 cellmotility) 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. RhoG-mediated Rac signalling has been shown to promote neurite outgrowth and cell migration in mammalian cells as well as phagocytosis of apoptotic cells in C. elegans.
^ abcdWennerberg K, Ellerbroek SM, Liu RY, Karnoub AE, Burridge K, Der CJ (December 2002). "RhoG signals in parallel with Rac1 and Cdc42". The Journal of Biological Chemistry. 277 (49): 47810–7. PMID12376551. doi:10.1074/jbc.M203816200.
^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-kappaB". Oncogene. 21 (2): 207–16. PMID11803464. doi:10.1038/sj.onc.1205036.
^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. PMID17570359. doi:10.1016/j.yexcr.2007.05.010.
^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. PMID10652265.
^Bellanger JM, Lazaro JB, Diriong S, Fernandez A, Lamb N, Debant A (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. PMID9464532. doi:10.1038/sj.onc.1201532.
^Estrach S, Schmidt S, Diriong S, Penna A, Blangy A, Fort P, Debant A (February 2002). "The Human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth". Current Biology. 12 (4): 307–12. PMID11864571. doi:10.1016/S0960-9822(02)00658-9.
^ abdeBakker CD, Haney LB, Kinchen JM, Grimsley C, Lu M, Klingele D, Hsu PK, Chou BK, Cheng LC, Blangy A, Sondek J, Hengartner MO, Wu YC, Ravichandran KS (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". Current Biology. 14 (24): 2208–16. PMID15620647. doi:10.1016/j.cub.2004.12.029.
^Zalcman G, Closson V, Camonis J, Honoré N, Rousseau-Merck MF, Tavitian A, Olofsson B (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". The Journal of Biological Chemistry. 271 (48): 30366–74. PMID8939998. doi:10.1074/jbc.271.48.30366.
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. PMID8325658. doi:10.1006/geno.1993.1271.
Prieto-Sánchez RM, Bustelo XR (September 2003). "Structural basis for the signaling specificity of RhoG and Rac1 GTPases". The Journal of Biological Chemistry. 278 (39): 37916–25. PMID12805377. doi:10.1074/jbc.M301437200.
Meller N, Merlot S, Guda C (November 2005). "CZH proteins: a new family of Rho-GEFs". Journal of Cell Science. 118 (Pt 21): 4937–46. PMID16254241. doi:10.1242/jcs.02671.
Lu M, Kinchen JM, Rossman KL, Grimsley C, Hall M, Sondek J, Hengartner MO, Yajnik V, Ravichandran KS (February 2005). "A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs". Current Biology. 15 (4): 371–7. PMID15723800. doi:10.1016/j.cub.2005.01.050.
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. PMID18601892. doi:10.1016/j.ab.2008.05.047.
Skowronek KR, Guo F, Zheng Y, Nassar N (September 2004). "The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids". The Journal of Biological Chemistry. 279 (36): 37895–907. PMID15199069. doi:10.1074/jbc.M312677200.
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. PMID17027967. doi:10.1016/j.yexcr.2006.09.006.
Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS (October 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. PMID11595183. doi:10.1016/S0092-8674(01)00520-7.