Biology:ARHGDIB

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene.[1][2][3] Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.[4]

Interactions

ARHGDIB has been shown to interact with VAV1[5] and Src.[6]

Gene family

RhoGDI2 (ARHGDIB) is part of a family of three members: RhoGDI1, RhoGDI2 (also known as RhoGDIB, D4-GDI or Ly-GDI) and RhoGDI3. RhoGDI1 is expressed in many organs and is the best studied member of the family.[7][8][9] RhoGDI2 was initially believed to be expressed specifically in blood forming cells,[2] but has subsequently been found to be highly expressed in a variety of other cell types as well.[10] RhoGDI3 is predominantly expressed in brain, lung, kidney, testis and pancreas,[11][12] and is targeted to specific parts of the cell such as the Golgi where it may play a role in transport or proteins in cells.[13][14]

Disease involvement

Despite a high degree of sequence similarity, RhoGDI1 and RhoGDI2 are very different in their binding affinities for specific GTPases,[15] and more importantly, in their roles in tumor formation and spread of tumor to other organs (the process of metastasis).[16] For example, RhoGDI2 functions as a suppressor of metastasis but not a tumor suppressor in bladder cancer cells,[10][17] while RhoGDI1 is a ubiquitous suppressor of tumor growth in all sites so far examined in bladder cancer models),[18] suggesting that their cellular functions must diverge to cause these differential effects.

While there are clear links between the alteration of RhoGDI2 protein levels and disease progression and/or metastasis in several types of cancer, the mechanistic underpinnings of the mode of RhoGDI2 action under carcinogenic cellular conditions are only now beginning to be understood. Evidence demonstrates that RhoGDI2 inhibits the endothelin axis and crosstalk with macrophages within the micrometastatic microenvironment to inhibit metastatic outgrowth.[19] As such, RhoGDI2 could prove important in the regulation of tumor dormancy. Targeting this axis with orally available endothelin receptor antagonists[20] may prove efficacious in mimicking the inhibitory role of RhoGDI2 by preventing macrophage infiltration into the micrometastatic niche.[21] Recent work has also determined that genetic and pharmacologic targeting of chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2, its receptor CCR2 and pharmacologic ablation of macrophages can also phenocopy the effect of RhoGDI2 expression to prevent metastatic colonization of the lung67 and that RhoGDI2 is suppressor of versican, a protein that has been shown to promote cell migration[22] and metastasis in several tumor models.

In contrast to its role as a metastasis suppressor in bladder cancer, in breast, RhoGDI2 expression has been reported to be upregulated in cancer[23] and to promote invasion of breast cancer cells,[24] while another report found a biphasic expression pattern of RhoGDI2 in breast cancer with decreased expression correlating with lymph node metastasis.[25]

ARHGDIB antibodies may be a marker for long-term kidney graft loss in recipients of deceased-donor kidneys.[26]

References

  1. ↑ "cDNA cloning of a human mRNA preferentially expressed in hematopoietic cells and with homology to a GDP-dissociation inhibitor for the rho GTP-binding proteins". Proc Natl Acad Sci U S A 90 (4): 1479–83. March 1993. doi:10.1073/pnas.90.4.1479. PMID 8434008. Bibcode: 1993PNAS...90.1479L. 
  2. ↑ 2.0 2.1 "Ly-GDI, a GDP-dissociation inhibitor of the RhoA GTP-binding protein, is expressed preferentially in lymphocytes". Proc Natl Acad Sci U S A 90 (16): 7568–72. September 1993. doi:10.1073/pnas.90.16.7568. PMID 8356058. Bibcode: 1993PNAS...90.7568S. 
  3. ↑ "Entrez Gene: ARHGDIB Rho GDP dissociation inhibitor (GDI) beta". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=397. 
  4. ↑ "Gene Cards: ARHGDIB". https://www.genecards.org/index.php?path=/Search/keyword/ARHGDIB. 
  5. ↑ "Vav, a GDP/GTP nucleotide exchange factor, interacts with GDIs, proteins that inhibit GDP/GTP dissociation". FEBS Lett. 467 (1): 75–80. February 2000. doi:10.1016/S0014-5793(00)01121-2. PMID 10664460. 
  6. ↑ "Src phosphorylation of RhoGDI2 regulates its metastasis suppressor function". Proc. Natl. Acad. Sci. U.S.A. 106 (14): 5807–12. April 2009. doi:10.1073/pnas.0810094106. PMID 19321744. Bibcode: 2009PNAS..106.5807W. 
  7. ↑ "GDIs: central regulatory molecules in Rho GTPase activation". Trends Cell Biol. 15 (7): 356–63. July 2005. doi:10.1016/j.tcb.2005.05.001. PMID 15921909. 
  8. ↑ "RhoGDI: multiple functions in the regulation of Rho family GTPase activities". Biochem. J. 390 (Pt 1): 1–9. August 2005. doi:10.1042/BJ20050104. PMID 16083425. 
  9. ↑ "The 'invisible hand': regulation of RHO GTPases by RHOGDIs". Nat. Rev. Mol. Cell Biol. 12 (8): 493–504. August 2011. doi:10.1038/nrm3153. PMID 21779026. 
  10. ↑ 10.0 10.1 "Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer". Clin. Cancer Res. 10 (11): 3800–6. June 2004. doi:10.1158/1078-0432.CCR-03-0653. PMID 15173088. 
  11. ↑ "RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas". Proc. Natl. Acad. Sci. U.S.A. 94 (9): 4279–84. April 1997. doi:10.1073/pnas.94.9.4279. PMID 9113980. Bibcode: 1997PNAS...94.4279A. 
  12. ↑ "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. November 1996. doi:10.1074/jbc.271.48.30366. PMID 8939998. 
  13. ↑ "RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain". Traffic 3 (5): 342–57. May 2002. doi:10.1034/j.1600-0854.2002.30504.x. PMID 11967128. 
  14. ↑ "Uncoupling of inhibitory and shuttling functions of rho GDP dissociation inhibitors". J. Biol. Chem. 280 (6): 4674–83. February 2005. doi:10.1074/jbc.M409741200. PMID 15513926. 
  15. ↑ "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Lett. 422 (2): 269–73. January 1998. doi:10.1016/S0014-5793(98)00020-9. PMID 9490022. 
  16. ↑ "RhoGDI signaling provides targets for cancer therapy". Eur. J. Cancer 46 (7): 1252–9. May 2010. doi:10.1016/j.ejca.2010.02.025. PMID 20347589. 
  17. ↑ "RhoGDI2 is an invasion and metastasis suppressor gene in human cancer". Cancer Res. 62 (22): 6418–23. November 2002. PMID 12438227. 
  18. ↑ "Rho GDP dissociation inhibitor 2 suppresses metastasis via unconventional regulation of RhoGTPases". Cancer Res. 69 (7): 2838–44. April 2009. doi:10.1158/0008-5472.CAN-08-1397. PMID 19276387. 
  19. ↑ "Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer". J. Clin. Invest. 121 (1): 132–47. January 2011. doi:10.1172/JCI42912. PMID 21183790. 
  20. ↑ "The endothelin axis: emerging role in cancer". Nat. Rev. Cancer 3 (2): 110–6. February 2003. doi:10.1038/nrc990. PMID 12563310. 
  21. ↑ "RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration". J. Clin. Invest. 122 (4): 1503–18. April 2012. doi:10.1172/JCI61392. PMID 22406535. 
  22. ↑ "Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration". Oncogene 27 (52): 6679–89. November 2008. doi:10.1038/onc.2008.264. PMID 18724390. 
  23. ↑ "Up-regulation of RhoGDI2 in human breast cancer and its prognostic implications". Cancer Res Treat 42 (3): 151–6. September 2010. doi:10.4143/crt.2010.42.3.151. PMID 20948920. 
  24. ↑ "D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness". Cancer Res. 66 (11): 5592–8. June 2006. doi:10.1158/0008-5472.CAN-05-4004. PMID 16740694. 
  25. ↑ "Biphasic expression of RhoGDI2 in the progression of breast cancer and its negative relation with lymph node metastasis". Oncol. Rep. 17 (6): 1383–9. June 2007. doi:10.3892/or.17.6.1383. PMID 17487395. 
  26. ↑ Kamburova, EG; Gruijters, ML; Kardol-Hoefnagel, T; Wisse, BW; Joosten, I; Allebes, WA; van der Meer, A; Hilbrands, LB et al. (13 June 2019). "Antibodies against ARHGDIB are associated with long-term kidney graft loss.". American Journal of Transplantation 19 (12): 3335–3344. doi:10.1111/ajt.15493. PMID 31194283. 

External links

Further reading



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