Biology:RhoG

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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. ↑ "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends in Cell Biology 16 (10): 522–9. October 2006. doi:10.1016/j.tcb.2006.08.006. PMID 16949823. 
  2. ↑ "Entrez Gene: RHOG ras homolog gene family, member G (rho G)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=391. 
  3. ↑ "Growth-regulated expression of rhoG, a new member of the ras homolog gene family". Molecular and Cellular Biology 12 (7): 3138–48. July 1992. doi:10.1128/mcb.12.7.3138. PMID 1620121. 
  4. ↑ 4.0 4.1 "RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs". Molecular Biology of the Cell 9 (6): 1379–94. June 1998. doi:10.1091/mbc.9.6.1379. PMID 9614181. 
  5. ↑ 5.0 5.1 "RhoG regulates the neutrophil NADPH oxidase". Journal of Immunology 176 (9): 5314–20. May 2006. doi:10.4049/jimmunol.176.9.5314. PMID 16621998. 
  6. ↑ 6.0 6.1 "RhoG regulates gene expression and the actin cytoskeleton in lymphocytes". Oncogene 22 (3): 330–42. January 2003. doi:10.1038/sj.onc.1206116. PMID 12545154. 
  7. ↑ 7.0 7.1 7.2 "Small GTPase RhoG is a key regulator for neurite outgrowth in PC12 cells". Molecular and Cellular Biology 20 (19): 7378–87. October 2000. doi:10.1128/MCB.20.19.7378-7387.2000. PMID 10982854. 
  8. ↑ 8.0 8.1 "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. September 2007. doi:10.1083/jcb.200612053. PMID 17875742. 
  9. ↑ 9.0 9.1 9.2 "Activation of Rac1 by RhoG regulates cell migration". Journal of Cell Science 119 (Pt 1): 56–65. January 2006. doi:10.1242/jcs.02720. PMID 16339170. 
  10. ↑ "Evolution of the Rho family of ras-like GTPases in eukaryotes". Molecular Biology and Evolution 24 (1): 203–16. January 2007. doi:10.1093/molbev/msl145. PMID 17035353. 
  11. ↑ 11.0 11.1 11.2 11.3 "RhoG signals in parallel with Rac1 and Cdc42". The Journal of Biological Chemistry 277 (49): 47810–7. December 2002. doi:10.1074/jbc.M203816200. PMID 12376551. 
  12. ↑ "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. January 2002. doi:10.1038/sj.onc.1205036. PMID 11803464. 
  13. ↑ "Involvement of the Rho/Rac family member RhoG in caveolar endocytosis". Oncogene 25 (21): 2961–73. May 2006. doi:10.1038/sj.onc.1209333. PMID 16568096. 
  14. ↑ "RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism". Experimental Cell Research 313 (13): 2821–32. August 2007. doi:10.1016/j.yexcr.2007.05.010. PMID 17570359. 
  15. ↑ "TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG". Journal of Cell Science 113 (Pt 4): 729–39. February 2000. doi:10.1242/jcs.113.4.729. PMID 10652265. 
  16. ↑ "The two guanine nucleotide exchange factor domains of Trio link the Rac1 and the RhoA pathways in vivo". Oncogene 16 (2): 147–52. January 1998. doi:10.1038/sj.onc.1201532. PMID 9464532. 
  17. ↑ "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. February 2002. doi:10.1016/S0960-9822(02)00658-9. PMID 11864571. 
  18. ↑ 18.0 18.1 "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. December 2004. doi:10.1016/j.cub.2004.12.029. PMID 15620647. 
  19. ↑ "SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis". Molecular Biology of the Cell 15 (7): 3309–19. July 2004. doi:10.1091/mbc.E04-02-0146. PMID 15133129. 
  20. ↑ "Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2". The EMBO Journal 17 (22): 6608–21. November 1998. doi:10.1093/emboj/17.22.6608. PMID 9822605. 
  21. ↑ "Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins". Molecular and Cellular Biology 19 (11): 7870–85. November 1999. doi:10.1128/mcb.19.11.7870. PMID 10523675. 
  22. ↑ "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. November 1996. doi:10.1074/jbc.271.48.30366. PMID 8939998. 
  23. ↑ "GEF what? Dock180 and related proteins help Rac to polarize cells in new ways". Trends in Cell Biology 17 (8): 383–93. August 2007. doi:10.1016/j.tcb.2007.05.001. PMID 17765544. 
  24. ↑ "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex". Nature Cell Biology 4 (8): 574–82. August 2002. doi:10.1038/ncb824. PMID 12134158. 
  25. ↑ "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nature Structural & Molecular Biology 11 (8): 756–62. August 2004. doi:10.1038/nsmb800. PMID 15247908. 
  26. ↑ "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature 424 (6947): 461–4. July 2003. doi:10.1038/nature01817. PMID 12879077. Bibcode: 2003Natur.424..461K. 
  27. ↑ "Kinectin is a key effector of RhoG microtubule-dependent cellular activity". Molecular and Cellular Biology 21 (23): 8022–34. December 2001. doi:10.1128/MCB.21.23.8022-8034.2001. PMID 11689693. 
  28. ↑ "PIST: a novel PDZ/coiled-coil domain binding partner for the rho-family GTPase TC10". Biochemical and Biophysical Research Communications 280 (2): 541–7. January 2001. doi:10.1006/bbrc.2000.4160. PMID 11162552. 
  29. ↑ "Kinectin is a key effector of RhoG microtubule-dependent cellular activity". Molecular and Cellular Biology 21 (23): 8022–34. December 2001. doi:10.1128/MCB.21.23.8022-8034.2001. PMID 11689693. 

Further reading




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