Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIBgene.[1][2][3] Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.[4]
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]
↑Groysman M, Russek CS, Katzav S (February 2000). "Vav, a GDP/GTP nucleotide exchange factor, interacts with GDIs, proteins that inhibit GDP/GTP dissociation". FEBS Lett. 467 (1): 75–80. doi:10.1016/S0014-5793(00)01121-2. PMID10664460.
↑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". J. Biol. Chem. 271 (48): 30366–74. doi:10.1074/jbc.271.48.30366. PMID8939998.
↑Brunet N, Morin A, Olofsson B (May 2002). "RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain". Traffic. 3 (5): 342–57. doi:10.1034/j.1600-0854.2002.30504.x. PMID11967128.
↑Dransart E, Morin A, Cherfils J, Olofsson B (February 2005). "Uncoupling of inhibitory and shuttling functions of rho GDP dissociation inhibitors". J. Biol. Chem. 280 (6): 4674–83. doi:10.1074/jbc.M409741200. PMID15513926.
↑Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P (January 1998). "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Lett. 422 (2): 269–73. doi:10.1016/S0014-5793(98)00020-9. PMID9490022.
↑Harding MA, Theodorescu D (May 2010). "RhoGDI signaling provides targets for cancer therapy". Eur. J. Cancer. 46 (7): 1252–9. doi:10.1016/j.ejca.2010.02.025. PMID20347589.
↑Gildea JJ, Seraj MJ, Oxford G, Harding MA, Hampton GM, Moskaluk CA, Frierson HF, Conaway MR, Theodorescu D (November 2002). "RhoGDI2 is an invasion and metastasis suppressor gene in human cancer". Cancer Res. 62 (22): 6418–23. PMID12438227.
↑Nelson J, Bagnato A, Battistini B, Nisen P (February 2003). "The endothelin axis: emerging role in cancer". Nat. Rev. Cancer. 3 (2): 110–6. doi:10.1038/nrc990. PMID12563310.
↑Zhang Y, Zhang B (June 2006). "D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness". Cancer Res. 66 (11): 5592–8. doi:10.1158/0008-5472.CAN-05-4004. PMID16740694.
↑Hu LD, Zou HF, Zhan SX, Cao KM (June 2007). "Biphasic expression of RhoGDI2 in the progression of breast cancer and its negative relation with lymph node metastasis". Oncol. Rep. 17 (6): 1383–9. doi:10.3892/or.17.6.1383. PMID17487395.
Aebersold R, Leavitt J (1990). "Sequence analysis of proteins separated by polyacrylamide gel electrophoresis: towards an integrated protein database". Electrophoresis. 11 (7): 517–27. doi:10.1002/elps.1150110702. PMID2226408.
Adra CN, Kobayashi H, Rowley JD, Lim B (1995). "Assignment of the human GDID4 gene, a GDP/GTP-exchange regulator, to chromosome 12p12.3". Genomics. 24 (1): 188–90. doi:10.1006/geno.1994.1601. PMID7896279.
Leffers H, Nielsen MS, Andersen AH, Honoré B, Madsen P, Vandekerckhove J, Celis JE (1994). "Identification of two human Rho GDP dissociation inhibitor proteins whose overexpression leads to disruption of the actin cytoskeleton". Exp. Cell Res. 209 (2): 165–74. doi:10.1006/excr.1993.1298. PMID8262133.
Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S, Takai Y (1997). "Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein". J. Biol. Chem. 272 (37): 23371–5. doi:10.1074/jbc.272.37.23371. PMID9287351.
Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P (1998). "Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity". FEBS Lett. 422 (2): 269–73. doi:10.1016/S0014-5793(98)00020-9. PMID9490022.
Scheffzek K, Stephan I, Jensen ON, Illenberger D, Gierschik P (2000). "The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI". Nat. Struct. Biol. 7 (2): 122–6. doi:10.1038/72392. PMID10655614.
Groysman M, Russek CS, Katzav S (2000). "Vav, a GDP/GTP nucleotide exchange factor, interacts with GDIs, proteins that inhibit GDP/GTP dissociation". FEBS Lett. 467 (1): 75–80. doi:10.1016/S0014-5793(00)01121-2. PMID10664460.
Kasper B, Tidow N, Grothues D, Welte K (2000). "Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI and RhoGDI) in neutrophils from patients with severe congenital neutropenia". Blood. 95 (9): 2947–53. PMID10779444.
Fauré J, Dagher MC (2001). "Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI)". Biochimie. 83 (5): 409–14. doi:10.1016/S0300-9084(01)01263-9. PMID11368848.
Kwon KB, Park EK, Ryu DG, Park BH (2003). "D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells". Exp. Mol. Med. 34 (1): 32–7. doi:10.1038/emm.2002.5. PMID11989976.
Thiede B, Siejak F, Dimmler C, Rudel T (2003). "Prediction of translocation and cleavage of heterogeneous ribonuclear proteins and Rho guanine nucleotide dissociation inhibitor 2 during apoptosis by subcellular proteome analysis". Proteomics. 2 (8): 996–1006. doi:10.1002/1615-9861(200208)2:8<996::AID-PROT996>3.0.CO;2-3. PMID12203895.
Groysman M, Hornstein I, Alcover A, Katzav S (2003). "Vav1 and Ly-GDI two regulators of Rho GTPases, function cooperatively as signal transducers in T cell antigen receptor-induced pathways". J. Biol. Chem. 277 (51): 50121–30. doi:10.1074/jbc.M204299200. PMID12386169.
