RhoG

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[5] and is encoded by the gene RHOG.[6]

RHOG
Identifiers
AliasesRHOG, ARHG, RhoG, ras homolog family member G
External IDsOMIM: 179505 MGI: 1928370 HomoloGene: 68196 GeneCards: RHOG
Gene location (Human)
Chr.Chromosome 11 (human)[1]
Band11p15.4Start3,826,978 bp[1]
End3,840,959 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
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 MbChr 7: 102.24 – 102.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

RhoG was first identified as a coding sequence upregulated in hamster lung fibroblasts upon stimulation with serum.[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] and HeLa 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]

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),[13] gene transcription,[10][16] endocytosis,[17] neurite outgrowth,[11] protection from anoikis[18] and regulation of the neutrophil NADPH oxidase.[9]

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[19] (via its GEFD1 domain) and also on RhoA[20] via a separate GEF domain (GEFD2). Activation of RhoG by TRIO has been shown to promote NGF-induced neurite outgrowth in PC12 cells[21] and phagocytosis of apoptotic cells in C. elegans.[22] 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[23] and apical cup assembly in endothelial cells (an important stage in leukocyte trans-endothelial migration).[12] Other GEFs reported to interact with RhoG include Dbs, ECT2, VAV2 and VAV3.[15][24][25]

There have been very few interactions reported between RhoG and negative regulators of G protein function. Examples include IQGAP2[15] and RhoGDI3.[26]

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.[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 protein ELMO (engulfment and cell motility)[28] 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.[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 in C. elegans.[22]

Other proteins known to bind RhoG in its GTP-bound state include the microtubule-associated protein kinectin,[31] Phospholipase D1 and the MAP Kinase activator MLK3.[15]

Interactions

RhoG has been shown to interact with KTN1.[32][33]

References

  1. GRCh38: Ensembl release 89: ENSG00000177105 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000073982 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. PMID 16949823.
  6. "Entrez Gene: RHOG ras homolog gene family, member G (rho G)".
  7. Vincent S, Jeanteur P, Fort P (July 1992). "Growth-regulated expression of rhoG, a new member of the ras homolog gene family". Molecular and Cellular Biology. 12 (7): 3138–48. doi:10.1128/mcb.12.7.3138. PMC 364528. PMID 1620121.
  8. Gauthier-Rouvière C, Vignal E, Mériane M, Roux P, Montcourier P, Fort P (June 1998). "RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs". Molecular Biology of the Cell. 9 (6): 1379–94. doi:10.1091/mbc.9.6.1379. PMC 25357. PMID 9614181.
  9. Condliffe AM, Webb LM, Ferguson GJ, Davidson K, Turner M, Vigorito E, Manifava M, Chilvers ER, Stephens LR, Hawkins PT (May 2006). "RhoG regulates the neutrophil NADPH oxidase". Journal of Immunology. 176 (9): 5314–20. doi:10.4049/jimmunol.176.9.5314. PMID 16621998.
  10. Vigorito E, Billadeu DD, Savoy D, McAdam S, Doody G, Fort P, Turner M (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.
  11. Katoh H, Yasui H, Yamaguchi Y, Aoki J, Fujita H, Mori K, Negishi M (October 2000). "Small GTPase RhoG is a key regulator for neurite outgrowth in PC12 cells". Molecular and Cellular Biology. 20 (19): 7378–87. doi:10.1128/MCB.20.19.7378-7387.2000. PMC 86291. PMID 10982854.
  12. van Buul JD, Allingham MJ, Samson T, Meller J, Boulter E, García-Mata R, Burridge K (September 2007). "RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration". The Journal of Cell Biology. 178 (7): 1279–93. doi:10.1083/jcb.200612053. PMC 2064659. PMID 17875742.
  13. Katoh H, Hiramoto K, Negishi M (January 2006). "Activation of Rac1 by RhoG regulates cell migration". Journal of Cell Science. 119 (Pt 1): 56–65. doi:10.1242/jcs.02720. PMID 16339170.
  14. Boureux A, Vignal E, Faure S, Fort P (January 2007). "Evolution of the Rho family of ras-like GTPases in eukaryotes". Molecular Biology and Evolution. 24 (1): 203–16. doi:10.1093/molbev/msl145. PMC 2665304. PMID 17035353.
  15. Wennerberg 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. doi:10.1074/jbc.M203816200. PMID 12376551.
  16. 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. doi:10.1038/sj.onc.1205036. PMID 11803464.
  17. Prieto-Sánchez 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.
  18. 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. PMID 17570359.
  19. 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. PMID 10652265.
  20. 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. doi:10.1038/sj.onc.1201532. PMID 9464532.
  21. 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. doi:10.1016/S0960-9822(02)00658-9. PMID 11864571. S2CID 14439106.
  22. deBakker 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. doi:10.1016/j.cub.2004.12.029. PMID 15620647. S2CID 1269946.
  23. Ellerbroek SM, Wennerberg K, Arthur WT, Dunty JM, Bowman DR, DeMali KA, Der C, Burridge K (July 2004). "SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis". Molecular Biology of the Cell. 15 (7): 3309–19. doi:10.1091/mbc.E04-02-0146. PMC 452585. PMID 15133129.
  24. Schuebel KE, Movilla N, Rosa JL, Bustelo XR (November 1998). "Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2". The EMBO Journal. 17 (22): 6608–21. doi:10.1093/emboj/17.22.6608. PMC 1171007. PMID 9822605.
  25. Movilla N, Bustelo XR (November 1999). "Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins". Molecular and Cellular Biology. 19 (11): 7870–85. doi:10.1128/mcb.19.11.7870. PMC 84867. PMID 10523675.
  26. 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. doi:10.1074/jbc.271.48.30366. PMID 8939998.
  27. Côté JF, Vuori K (August 2007). "GEF what? Dock180 and related proteins help Rac to polarize cells in new ways". Trends in Cell Biology. 17 (8): 383–93. doi:10.1016/j.tcb.2007.05.001. PMC 2887429. PMID 17765544.
  28. 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. PMID 12134158. S2CID 36363774.
  29. 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. PMID 15247908. S2CID 125990.
  30. Katoh H, Negishi M (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature. 424 (6947): 461–4. doi:10.1038/nature01817. PMID 12879077. S2CID 4411133.
  31. Vignal E, Blangy A, Martin M, Gauthier-Rouvière C, Fort P (December 2001). "Kinectin is a key effector of RhoG microtubule-dependent cellular activity". Molecular and Cellular Biology. 21 (23): 8022–34. doi:10.1128/MCB.21.23.8022-8034.2001. PMC 99969. PMID 11689693.
  32. 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. PMID 11162552.
  33. Vignal E, Blangy A, Martin M, Gauthier-Rouvière C, Fort P (December 2001). "Kinectin is a key effector of RhoG microtubule-dependent cellular activity". Molecular and Cellular Biology. 21 (23): 8022–34. doi:10.1128/MCB.21.23.8022-8034.2001. PMC 99969. PMID 11689693.

Further reading

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