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RhoGDIs in Cancer

  • Anthony N. Anselmo
  • Gary M. Bokoch
  • Céline DerMardirossian
Chapter

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).

Keywords

Acute Myeloid Leukemia Chronic Lymphocytic Leukemia Phosphatidic Acid Raji Cell T24T Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. DerMardirossian, C., and G.M. Bokoch. 2005. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 15:356–63.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. DerMardirossian, C., A. Schnelzer, and G.M. Bokoch. 2004. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell. 15:117–27.CrossRefPubMedGoogle Scholar
  14. Dovas, A., and J.R. Couchman. 2005. RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J. 390:1–9.CrossRefPubMedGoogle Scholar
  15. Dransart, E., A. Morin, J. Cherfils, and B. Olofsson. 2004. Uncoupling of inhibitory and shuttling functions of rhoGDIs. J.Biol Chem. 280:4674–4683.CrossRefPubMedGoogle Scholar
  16. Dransart, E., B. Olofsson, and J. Cherfils. 2005. RhoGDIs revisited: novel roles in Rho regulation. Traffic. 6:957–66.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. Hanahan, D., and R.A. Weinberg. 2000. The hallmarks of cancer. Cell. 100:57–70.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. Sassano, A., and L.C. Platanias. 2008. Statins in tumor suppression. Cancer Lett. 260:11–9.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.Google Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. Zhang, Y., and B. Zhang. 2006. D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66:5592–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Anthony N. Anselmo
    • 1
  • Gary M. Bokoch
    • 1
  • Céline DerMardirossian
    • 1
  1. 1.Departments of Immunology and Cell BiologyThe Scripps Research InstituteLa JollaUSA

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