Abstract
The dynamics of Rho GTPase action are regulated by both an activity cycle and a cytosol-to-membrane cycle (Fig. 3.1). Rho GTPases are activated by the exchange of bound GDP for ambient GTP, which is stimulated by guanine nucleotide exchange factors (GEFs) and are inactivated by hydrolysis of bound GTP to GDP catalyzed by GTPase-activating proteins (GAPs). This activity cycle is regulated by guanine nucleotide dissociation inhibitors (GDIs), which act to sterically shield the Rho GTPases from the action of GEFs and GAPs. Thus for Rho GTPases to become active, it is thought that they must first be released from GDIs in order for membrane-associated GEFs to catalyze activation. Superimposed on this activity cycle is a cytosol/membrane cycle that is directly controlled by Rho GDIs (see below).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adra, C.N., D. Manor, J.L. Ko, S. Zhu, T. Horiuchi, L. Van Aelst, R.A. Cerione, and B. Lim. 1997. RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proc Natl Acad Sci U S A. 94:4279–84.
Agarwal, B., S. Bhendwal, B. Halmos, S.F. Moss, W.G. Ramey, and P.R. Holt. 1999. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res. 5:2223–9.
Allenspach, E.J., P. Cullinan, J. Tong, Q. Tang, A.G. Tesciuba, J.L. Cannon, S.M. Takahashi, R. Morgan, J.K. Burkhardt, and A.I. Sperling. 2001. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity. 15:739–50.
Blackhall, F.H., D.A. Wigle, I. Jurisica, M. Pintilie, N. Liu, G. Darling, M.R. Johnston, S. Keshavjee, T. Waddell, T. Winton, F.A. Shepherd, and M.S. Tsao. 2004. Validating the prognostic value of marker genes derived from a non-small cell lung cancer microarray study. Lung Cancer. 46:197–204.
Bourmeyster, N., M.J. Stasia, J. Garin, J. Gagnon, P. Boquet, and P.V. Vignais. 1992. Copurification of rho protein and the rho-GDP dissociation inhibitor from bovine neutrophil cytosol. Effect of phosphoinositides on rho ADP-ribosylation by the C3 exoenzyme of Clostridium botulinum. Biochemistry. 31:12863–9.
Bourmeyster, N., and P.V. Vignais. 1996. Phosphorylation of Rho GDI stabilizes the Rho A-Rho GDI complex in neutrophil cytosol. Biochem Biophys Res Commun. 218:54–60.
Campostrini, N., D. Marimpietri, A. Totolo, C. Mancone, G.M. Fimia, M. Ponzoni, and P.G. Righetti. 2006. Proteomic analysis of anti-angiogenic effects by a combined treatment with vinblastine and rapamycin in an endothelial cell line. Proteomics. 6:4420–31.
Chapman-Shimshoni, D., M. Yuklea, J. Radnay, H. Shapiro, and M. Lishner. 2003. Simvastatin induces apoptosis of B-CLL cells by activation of mitochondrial caspase 9. Exp Hematol. 31:779–83.
Chuang, T.H., B.P. Bohl, and G.M. Bokoch. 1993. Biologically-active lipids are regulators of Rac-GDI complexation. J.Biol.Chem. 268:26206–26211.
Cordle, A., J. Koenigsknecht-Talboo, B. Wilkinson, A. Limpert, and G. Landreth. 2005. Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem. 280:34202–9.
DerMardirossian, C., and G.M. Bokoch. 2005. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 15:356–63.
DerMardirossian, C., G. Rocklin, J.Y. Seo, and G.M. Bokoch. 2006. Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling. Mol Biol Cell. 17:4760–8.
DerMardirossian, C., A. Schnelzer, and G.M. Bokoch. 2004. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell. 15:117–27.
Dovas, A., and J.R. Couchman. 2005. RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J. 390:1–9.
Dransart, E., A. Morin, J. Cherfils, and B. Olofsson. 2004. Uncoupling of inhibitory and shuttling functions of rhoGDIs. J.Biol Chem. 280:4674–4683.
Dransart, E., B. Olofsson, and J. Cherfils. 2005. RhoGDIs revisited: novel roles in Rho regulation. Traffic. 6:957–66.
Faure, J., P.V. Vignais, and M.C. Dagher. 1999. Phosphoinositide-dependent activation of Rho A involves partial opening of the RhoA/Rho-GDI complex. Eur J Biochem. 262:879–89.
Fukumoto, Y., K. Kaibuchi, Y. Hori, H. Fujioka, S. Araki, T. Ueda, A. Kikuchi, and Y. Takai. 1990. Molecular-cloning and characterization of a novel type of regulatory protein (GDI) for the Rho proteins, Ras p21-like small GTP-binding proteins. Oncogene. 5:1321–1328.
Gildea, J.J., M.J. Seraj, G. Oxford, M.A. Harding, G.M. Hampton, C.A. Moskaluk, H.F. Frierson, M.R. Conaway, and D. Theodorescu. 2002. RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 62:6418–23.
Gorvel, J.P., T.C. Chang, J. Boretto, T. Azuma, and P. Chavrier. 1998. Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and Rho GTPase selectivity. FEBS Lett. 422:269–273.
Gosser, Y.Q., T.K. Nomanbhoy, B. Aghazadeh, D. Manor, C. Combs, R.A. Cerione, and M.K. Rosen. 1997. C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases. Nature. 387:814–819.
Goto, T., M. Takano, M. Sakamoto, A. Kondo, J. Hirata, T. Kita, H. Tsuda, Y. Tenjin, and Y. Kikuchi. 2006. Gene expression profiles with cDNA microarray reveal RhoGDI as a predictive marker for paclitaxel resistance in ovarian cancers. Oncol Rep. 15:1265–71.
Grizot, S., J. Faure, F. Fieschi, P.V. Vignais, M.C. Dagher, and E. Pebay-Peyroula. 2001. Crystal structure of the Rac1-RhoGDI complex involved in NADPH oxidase activation. Biochemistry. 40:10007–10013.
Hanahan, D., and R.A. Weinberg. 2000. The hallmarks of cancer. Cell. 100:57–70.
Hoffman, G.R., N. Nassar, and R.A. Cerione. 2000. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell. 100:345–56.
Hori, Y., A. Kikuchi, M. Isomura, M. Katayama, Y. Miura, H. Fujioka, K. Kaibuchi, and Y. Takai. 1991. Post-translational modifications of the C-terminal region of the rho protein are important for its interaction with membranes and the stimulatory and inhibitory GDP/GTP exchange proteins. Oncogene. 6:515–22.
Jiang, W.G., G. Watkins, J. Lane, G.H. Cunnick, A. Douglas-Jones, K. Mokbel, and R.E. Mansel. 2003. Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin Cancer Res. 9:6432–40.
Jones, M.B., H. Krutzsch, H. Shu, Y. Zhao, L.A. Liotta, E.C. Kohn, and E.F. Petricoin, 3rd. 2002. Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer. Proteomics. 2:76–84.
Keep, N.H., M. Barnes, I. Barsukov, R. Badii, L.Y. Lian, A.W. Segal, P.C. Moody, and G.C. Roberts. 1997. A modulator of rho family G proteins, rhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. Structure. 5:623–33.
Khurana, V., A. Sheth, G. Caldito, and J.S. Barkin. 2007. Statins reduce the risk of pancreatic cancer in humans: a case-control study of half a million veterans. Pancreas. 34:260–5.
Kim, O., J. Yang, and Y. Qiu. 2002. Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain. J.Biol Chem. 277:30066–30071.
Krieser, R.J., and A. Eastman. 1999. Cleavage and nuclear translocation of the caspase 3 substrate Rho GDP-dissociation inhibitor, D4-GDI, during apoptosis. Cell Death Differ. 6:412–9.
Kwon, K.B., E.K. Park, D.G. Ryu, and B.H. Park. 2002. D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells. Exp Mol Med. 34:32–7.
Lelias, J.M., C.N. Adra, G.M. Wulf, J.C. Guillemot, M. Khagad, D. Caput, and B. Lim. 1993. 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. 90:1479–83.
Leonard, D., M.J. Hart, J.V. Platko, A. Eva, W. Henzel, T. Evans, and R.A. Cerione. 1992. The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein. J Biol Chem. 267:22860–8.
Longenecker, K., P. Read, U. Derewenda, Z. Dauter, X. Liu, S. Garrard, L. Walker, A.V. Somlyo, R.K. Nakamoto, A.P. Somlyo, and Z.S. Derewenda. 1999. How RhoGDI binds Rho. Acta Crystallogr D Biol Crystallogr. 55 (Pt 9):1503–15.
Mehta, D., A. Rahman, and A.B. Malik. 2001. Protein kinase C-alpha signals Rho-guanine nucleotide dissociation inhibitor phosphorylation and Rho activation and regulates the endothelial cell barrier function. J.Biol.Chem. 276:22614–22620.
Na, S., T.H. Chuang, A. Cunningham, T.G. Turi, J.H. Hanke, G.M. Bokoch, and D.E. Danley. 1996. D4-GDI, a substrate of CPP32, is proteolyzed during Fas-induced apoptosis. J Biol Chem. 271:11209–13.
Nakata, Y., K. Kondoh, S. Fukushima, A. Hashiguchi, W. Du, M. Hayashi, J. Fujimoto, J. Hata, and T. Yamada. 2008. Mutated D4-guanine diphosphate-dissociation inhibitor is found in human leukemic cells and promotes leukemic cell invasion. Exp Hematol. 36:37–50.
Nomanbhoy, T.K., and R.A. Cerione. 1996. Characterization of the interaction between RhoGDI and Cdc42Hs using fluorescence spectroscopy. J.Biol Chem. 271:10004–10009.
Reimer, J., S. Bien, J. Sonnemann, J.F. Beck, T. Wieland, H.K. Kroemer, and C.A. Ritter. 2007. Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells. Anticancer Drugs. 18:333–40.
Sassano, A., and L.C. Platanias. 2008. Statins in tumor suppression. Cancer Lett. 260:11–9.
Scheffzek, K., I. Stephan, O.N. Jensen, D. Illenberger, and P. Gierschik. 2000. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI. Nat.Struct.Biol. 7:122–126.
Schunke, D., P. Span, H. Ronneburg, A. Dittmer, M. Vetter, H.J. Holzhausen, E. Kantelhardt, S. Krenkel, V. Muller, F.C. Sweep, C. Thomssen, and J. Dittmer. 2007. Cyclooxygenase-2 is a target gene of rho GDP dissociation inhibitor beta in breast cancer cells. Cancer Res. 67:10694–702.
Takahashi, K., T. Sasaki, A. Mammoto, K. Takaishi, T. Kameyama, S. Tsukita, S. Tsukita, and Y. Takai. 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. 272:23371–23375.
Theodorescu, D., L.M. Sapinoso, M.R. Conaway, G. Oxford, G.M. Hampton, and H.F. Frierson, Jr. 2004. Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer. Clin Cancer Res. 10:3800–6.
Togawa, A., J. Miyoshi, H. Ishizaki, M. Tanaka, A. Takakura, H. Nishioka, H. Yoshida, T. Doi, A. Mizoguchi, N. Matsuura, Y. Niho, Y. Nishimune, S. Nishikawa, and Y. Takai. 1999. Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha. Oncogene. 18:5373–80.
Turner, S.J., S. Zhuang, T. Zhang, G.R. Boss, and R.B. Pilz. 2008. Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors. Biochem Pharmacol. 75:405–13.
Ugolev, Y., S. Molshanski-Mor, C. Weinbaum, and E. Pick. 2006. Liposomes comprising anionic but not neutral phospholipids cause dissociation of [Rac(1 or 2)-RhoGDI] complexes and support amphiphile-independent NADPH oxidase activation by such complexes. J Biol Chem. May 15, 2006, e pub ahead of print; URL: PM16702219.
Vincent, L., P. Albanese, H. Bompais, G. Uzan, J.P. Vannier, P.G. Steg, J. Soria, and C. Soria. 2003. Insights in the molecular mechanisms of the anti-angiogenic effect of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Thromb Haemost. 89:530–7.
Wu, Y., Moissoglu, K., Wang, H., Wang, X., Frierson, H.F., Schwartz, M.A., Theodorescu, D. 2009. Src phosphorylation of RhoGDI2 regulates its metastasis suppressor function. Proc Natl Acad Sci U S A. 7:106(14):5807–12.
Xia, Z., M.M. Tan, W.W. Wong, J. Dimitroulakos, M.D. Minden, and L.Z. Penn. 2001. Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia. 15:1398–407.
Yamashita, T., and M. Tohyama. 2003. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat.Neurosci. 6:461–467.
Zalcman, G., V. Closson, J. Camonis, N. Honore, M.F. Rousseau-Merck, A. Tavitian, and B. Olofsson. 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 30366–30374.
Zhang, B., Y. Zhang, M.C. Dagher, and E. Shacter. 2005. Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 65:6054–62.
Zhang, Y., and B. Zhang. 2006. D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66:5592–8.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Anselmo, A.N., Bokoch, G.M., DerMardirossian, C. (2010). RhoGDIs in Cancer. In: Golen, K. (eds) The Rho GTPases in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1111-7_3
Download citation
DOI: https://doi.org/10.1007/978-1-4419-1111-7_3
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-1110-0
Online ISBN: 978-1-4419-1111-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)