GDIs: central regulatory molecules in Rho GTPase activation.

The GDP dissociation inhibitors (GDIs) are pivotal regulators of Rho GTPase function. GDIs control the access of Rho GTPases to regulatory guanine nucleotide exchange factors and GTPase-activating proteins, to effector targets and to membranes where such effectors reside. We discuss here our current understanding of how Rho GTPase-GDI complexes are regulated by various proteins, lipids and enzymes that exert GDI displacement activity. We propose that phosphorylation mediated by diverse kinases might provide a means of controlling and coordinating Rho GTPase activation.

[1]  J. Erickson,et al.  Kinetics of Cdc42 membrane extraction by Rho-GDI monitored by real-time fluorescence resonance energy transfer. , 1999, Biochemistry.

[2]  J. Camonis,et al.  RhoGAPs and RhoGDIs, (His)stories of two families. , 1999, Progress in molecular and subcellular biology.

[3]  I. Vetter,et al.  Crystal structure of Rnd3/RhoE: functional implications 1 , 2002, FEBS letters.

[4]  C. Dermardirossian,et al.  Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. , 2004, Molecular cell.

[5]  L. Cantley,et al.  Characterization of a Rac1- and RhoGDI-Associated Lipid Kinase Signaling Complex , 1998, Molecular and Cellular Biology.

[6]  C. Wollheim,et al.  Characterization of small-molecular-mass guanine-nucleotide-binding regulatory proteins in insulin-secreting cells and PC12 cells. , 1992, European journal of biochemistry.

[7]  C. Cheney,et al.  A Drosophila homolog of bovine smg p25a GDP dissociation inhibitor undergoes a shift in isoelectric point in the developmental mutant quartet. , 1993, Molecular and cellular biology.

[8]  P. Chavrier,et al.  Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity , 1998, FEBS letters.

[9]  A. Shisheva,et al.  General role of GDP dissociation inhibitor 2 in membrane release of Rab proteins: modulations of its functional interactions by in vitro and in vivo structural modifications. , 1999, Biochemistry.

[10]  K. Kaibuchi,et al.  Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. , 1990, Oncogene.

[11]  T. Horiuchi,et al.  RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Takahashi,et al.  ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. , 2001, Immunity.

[13]  I. Vetter,et al.  The Guanine Nucleotide-Binding Switch in Three Dimensions , 2001, Science.

[14]  G M Bokoch,et al.  Biologically active lipids are regulators of Rac.GDI complexation. , 1993, The Journal of biological chemistry.

[15]  J. Ngsee,et al.  Isolation and Characterization of a Dual Prenylated Rab and VAMP2 Receptor* , 1997, The Journal of Biological Chemistry.

[16]  C. Burd,et al.  Molecular Dissection of Guanine Nucleotide Dissociation Inhibitor Function in Vivo , 1999, The Journal of Biological Chemistry.

[17]  P. Casey,et al.  Protein prenylation: molecular mechanisms and functional consequences. , 1996, Annual review of biochemistry.

[18]  R. Cerione,et al.  Fluorescence assays of Cdc42 interactions with target/effector proteins. , 1999, Biochemistry.

[19]  M. Karin,et al.  The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. , 2001, Molecular cell.

[20]  G M Bokoch,et al.  Guanine nucleotide exchange regulates membrane translocation of Rac/Rho GTP-binding proteins. , 1994, The Journal of biological chemistry.

[21]  T. Sasaki,et al.  Consequences of weak interaction of rho GDI with the GTP-bound forms of rho p21 and rac p21. , 1993, The Journal of biological chemistry.

[22]  G. Watkins,et al.  Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[23]  I. Just,et al.  Tissue-specific variations in the expression and regulation of the small GTP-binding protein Rho. , 1994, Biochimica et biophysica acta.

[24]  A. Mammoto,et al.  Direct Interaction of the Rho GDP Dissociation Inhibitor with Ezrin/Radixin/Moesin Initiates the Activation of the Rho Small G Protein* , 1997, The Journal of Biological Chemistry.

[25]  David Michaelson,et al.  Differential Localization of Rho Gtpases in Live Cells , 2001, The Journal of cell biology.

[26]  Y. Qiu,et al.  Selective Activation of Small GTPase RhoA by Tyrosine Kinase Etk through Its Pleckstrin Homology Domain* , 2002, The Journal of Biological Chemistry.

[27]  M. Sutcliffe,et al.  Definition of the switch surface in the solution structure of Cdc42Hs. , 1997, Biochemistry.

[28]  J. Cherfils,et al.  Uncoupling of Inhibitory and Shuttling Functions of Rho GDP Dissociation Inhibitors* , 2005, Journal of Biological Chemistry.

[29]  D. Gingras,et al.  Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes. , 2002, The Biochemical journal.

[30]  Y. Takai,et al.  Purification and characterization from bovine brain cytosol of a novel regulatory protein inhibiting the dissociation of GDP from and the subsequent binding of GTP to rhoB p20, a ras p21-like GTP-binding protein. , 1990, The Journal of biological chemistry.

[31]  A. Ridley,et al.  The small GTP-binding protein rac regulates growth factor-induced membrane ruffling , 1992, Cell.

[32]  M. Dagher,et al.  Phosphoinositide-dependent activation of Rho A involves partial opening of the RhoA/Rho-GDI complex. , 1999, European journal of biochemistry.

[33]  A. Malik,et al.  Protein Kinase C-α Signals Rho-Guanine Nucleotide Dissociation Inhibitor Phosphorylation and Rho Activation and Regulates the Endothelial Cell Barrier Function* , 2001, The Journal of Biological Chemistry.

[34]  A. Hall,et al.  Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. , 2002, Genes & development.

[35]  Gregory R. Hoffman,et al.  Structure of the Rho Family GTP-Binding Protein Cdc42 in Complex with the Multifunctional Regulator RhoGDI , 2000, Cell.

[36]  E. Kohn,et al.  Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer , 2002, Proteomics.

[37]  G. Roberts,et al.  A modulator of rho family G proteins, rhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. , 1997, Structure.

[38]  K. Scheffzek,et al.  The Rac–RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI , 2000, Nature Structural Biology.

[39]  R. Stancou,et al.  Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. , 1996, The EMBO journal.

[40]  W. Balch,et al.  Organization of the Rab‐GDI/CHM Superfamily: The Functional Basis for Choroideremia Disease , 2001, Traffic.

[41]  John G. Collard,et al.  Tumor-related Alternatively Spliced Rac1b Is Not Regulated by Rho-GDP Dissociation Inhibitors and Exhibits Selective Downstream Signaling* , 2003, Journal of Biological Chemistry.

[42]  Bruno Antonny,et al.  Dissociation of GDP Dissociation Inhibitor and Membrane Translocation Are Required for Efficient Activation of Rac by the Dbl Homology-Pleckstrin Homology Region of Tiam* , 2003, The Journal of Biological Chemistry.

[43]  T. Yamashita,et al.  The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI , 2003, Nature Neuroscience.

[44]  J. Garin,et al.  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. , 1992, Biochemistry.

[45]  W. J. Wu,et al.  Epidermal Growth Factor-dependent Regulation of Cdc42 Is Mediated by the Src Tyrosine Kinase* , 2003, Journal of Biological Chemistry.

[46]  T. Sasaki,et al.  The Rho small G protein family-Rho GDI system as a temporal and spatial determinant for cytoskeletal control. , 1998, Biochemical and biophysical research communications.

[47]  S. Grizot,et al.  Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation. , 2001, Biochemistry.

[48]  J. Lélias,et al.  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. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Pfeffer,et al.  Rab GDP Dissociation Inhibitor: Putting Rab GTPases in the Right Place (*) , 1995, The Journal of Biological Chemistry.

[50]  G M Bokoch,et al.  GDP dissociation inhibitor prevents intrinsic and GTPase activating protein-stimulated GTP hydrolysis by the Rac GTP-binding protein. , 1993, The Journal of biological chemistry.

[51]  J. Platko,et al.  The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein. , 1992, The Journal of biological chemistry.

[52]  J. Camonis,et al.  RhoGDI-3 Is a New GDP Dissociation Inhibitor (GDI) , 1996, The Journal of Biological Chemistry.

[53]  W. Balch,et al.  Rab‐αGDI activity is regulated by a Hsp90 chaperone complex , 2002 .

[54]  A. Alcover,et al.  Vav1 and Ly-GDI Two Regulators of Rho GTPases, Function Cooperatively as Signal Transducers in T Cell Antigen Receptor-induced Pathways* , 2002, The Journal of Biological Chemistry.

[55]  C. Der,et al.  Protein prenylation: more than just glue? , 1992, Current opinion in cell biology.

[56]  L. Staudt,et al.  Ly-GDI, a GDP-dissociation inhibitor of the RhoA GTP-binding protein, is expressed preferentially in lymphocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Seabra,et al.  Controlling the location and activation of Rab GTPases. , 2004, Current opinion in cell biology.

[58]  S. Pfeffer,et al.  Yip3 catalyses the dissociation of endosomal Rab–GDI complexes , 2003, Nature.

[59]  M. Dagher,et al.  Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI). , 2001, Biochimie.

[60]  D. Danley,et al.  Defective Rho GTPase regulation by IL-1 beta-converting enzyme-mediated cleavage of D4 GDP dissociation inhibitor. , 1996, Journal of immunology.

[61]  S. Nishikawa,et al.  Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα , 1999, Oncogene.

[62]  Richard A. Cerione,et al.  Characterization of the Interaction between RhoGDI and Cdc42Hs Using Fluorescence Spectroscopy (*) , 1996, The Journal of Biological Chemistry.

[63]  D. Danley,et al.  D4-GDI, a Substrate of CPP32, Is Proteolyzed during Fas-induced Apoptosis (*) , 1996, Journal of Biological Chemistry.

[64]  C. Moskaluk,et al.  RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. , 2002, Cancer research.

[65]  E. Ross Guanine Nucleotide Exchange Factors , 2002 .

[66]  L. Staudt,et al.  Immune responses in mice deficient in Ly-GDI, a lymphoid-specific regulator of Rho GTPases. , 1997, Molecular immunology.

[67]  R. Cerione,et al.  Cdc42: new roads to travel. , 2004, Trends in cell biology.

[68]  L. Lim,et al.  The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts , 1995, Molecular and cellular biology.

[69]  K. Longenecker,et al.  How RhoGDI binds Rho. , 1999, Acta crystallographica. Section D, Biological crystallography.

[70]  L. Van Aelst,et al.  Rho GTPases and signaling networks. , 1997, Genes & development.

[71]  R. Shaw,et al.  A single residue can modify target-binding affinity and activity of the functional domain of the Rho-subfamily GDP dissociation inhibitors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[72]  K. Welte,et al.  Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI and RhoGDI) in neutrophils from patients with severe congenital neutropenia. , 2000, Blood.

[73]  W. Balch,et al.  Rab-alphaGDI activity is regulated by a Hsp90 chaperone complex. , 2002, The EMBO journal.

[74]  K. Kaibuchi,et al.  Both stimulatory and inhibitory GDP/GTP exchange proteins, smg GDS and rho GDI, are active on multiple small GTP-binding proteins. , 1992, Biochemical and biophysical research communications.

[75]  S. Pfeffer,et al.  Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab–GDI , 1997, The EMBO journal.

[76]  T. Sasaki,et al.  The Dbl oncogene product as a GDP/GTP exchange protein for the Rho family: its properties in comparison with those of Smg GDS. , 1994, Biochemical and biophysical research communications.

[77]  M. J. Clague,et al.  Phosphorylation of GDI and membrane cycling of rab proteins , 1993, FEBS letters.

[78]  B. Olofsson,et al.  Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. , 1999, Cellular signalling.

[79]  T. Sasaki,et al.  Post-translational processing of rac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase. , 1992, The Journal of biological chemistry.

[80]  P. Hawkins,et al.  Activation of the small GTP-binding proteins rho and rac by growth factor receptors. , 1995, Journal of cell science.

[81]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992 .

[82]  A. Hall,et al.  Rho GTPases and their effector proteins. , 2000, The Biochemical journal.

[83]  S. Grizot,et al.  Mechanism of NADPH oxidase activation by the Rac/Rho-GDI complex. , 2001, Biochemistry.

[84]  M. Hirshberg,et al.  The crystal structure of human rac1, a member of the rho-family complexed with a GTP analogue , 1997, Nature Structural Biology.

[85]  P. Vignais,et al.  Phosphorylation of Rho GDI stabilizes the Rho A-Rho GDI complex in neutrophil cytosol. , 1996, Biochemical and Biophysical Research Communications - BBRC.

[86]  M. Rosen,et al.  C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases , 1997, Nature.