guanine nucleotide dissociation inhibitors


Summary: Protein factors that inhibit the dissociation of GDP from GTP-BINDING PROTEINS.

Top Publications

  1. Luan P, Balch W, Emr S, Burd C. Molecular dissection of guanine nucleotide dissociation inhibitor function in vivo. Rab-independent binding to membranes and role of Rab recycling factors. J Biol Chem. 1999;274:14806-17 pubmed
  2. Fei F, Kweon S, Haataja L, de Sepulveda P, Groffen J, Heisterkamp N. The Fer tyrosine kinase regulates interactions of Rho GDP-Dissociation Inhibitor ? with the small GTPase Rac. BMC Biochem. 2010;11:48 pubmed publisher
    ..These results identify tyrosine phosphorylation of RhoGDI? by Fer as a mechanism to regulate binding of RhoGDI? to Rac. ..
  3. Dovas A, Choi Y, Yoneda A, Multhaupt H, Kwon S, Kang D, et al. Serine 34 phosphorylation of rho guanine dissociation inhibitor (RhoGDIalpha) links signaling from conventional protein kinase C to RhoGTPase in cell adhesion. J Biol Chem. 2010;285:23296-308 pubmed publisher
    ..Together with fluorescence resonance energy transfer microscopy sensing GTP-RhoA levels, the data reveal a common pathway in cell adhesion linking two essential mediators, conventional PKC and RhoA. ..
  4. D Adamo P, Wolfer D, Kopp C, Tobler I, Toniolo D, Lipp H. Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1. Eur J Neurosci. 2004;19:1895-905 pubmed
    ..Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed. ..
  5. Theodorescu D, Sapinoso L, Conaway M, Oxford G, Hampton G, Frierson H. Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer. Clin Cancer Res. 2004;10:3800-6 pubmed
    ..03). These results suggest that RhoGDI2 is an independent predictor of prognosis for patients with bladder cancer and provide clinical evidence in support of its involvement in cancer metastasis. ..
  6. Siegrist S, Doe C. Microtubule-induced Pins/Galphai cortical polarity in Drosophila neuroblasts. Cell. 2005;123:1323-35 pubmed
    ..These results identify a role for microtubules in polarizing the neuroblast cortex, a fundamental step for generating cell diversity through asymmetric cell division. ..
  7. Huang C, You J, Wu M, Hsu K. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004;279:12286-92 pubmed
    ..These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors. ..
  8. Goody R, Rak A, Alexandrov K. The structural and mechanistic basis for recycling of Rab proteins between membrane compartments. Cell Mol Life Sci. 2005;62:1657-70 pubmed
    ..Here, the structural and mechanistic basis of events occurring in Rab delivery and cycling, and the differences between REP and GDI are discussed on the basis of recent advances in the field. ..
  9. Faure J, Dagher M. Interactions between Rho GTPases and Rho GDP dissociation inhibitor (Rho-GDI). Biochimie. 2001;83:409-14 pubmed
    ..The C-terminal polybasic region of RhoA was also shown to be a site of protein-protein interaction with Rho-GDI. ..

More Information


  1. Machner M, Isberg R. A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science. 2007;318:974-7 pubmed
    ..Thus, GDF and GEF activity can be promoted by a single protein, and GDF activity can coordinate Rab1 recruitment from the GDI-bound pool. ..
  2. Speicher S, Fischer A, Knoblich J, Carmena A. The PDZ protein Canoe regulates the asymmetric division of Drosophila neuroblasts and muscle progenitors. Curr Biol. 2008;18:831-7 pubmed publisher
  3. Bianchi V, Farisello P, Baldelli P, Meskenaite V, Milanese M, Vecellio M, et al. Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training. Hum Mol Genet. 2009;18:105-17 pubmed publisher
    ..This implies that an intact RP of SVs is necessary for memory processing under challenging conditions in mice. The possibility to correct the learning deficit in mice may have clinical implication for future studies in human. ..
  4. Slaughter B, Das A, Schwartz J, Rubinstein B, Li R. Dual modes of cdc42 recycling fine-tune polarized morphogenesis. Dev Cell. 2009;17:823-35 pubmed publisher
  5. Garcia Marcos M, Ghosh P, Ear J, Farquhar M. A structural determinant that renders G alpha(i) sensitive to activation by GIV/girdin is required to promote cell migration. J Biol Chem. 2010;285:12765-77 pubmed publisher
  6. Eitzen G, Will E, Gallwitz D, Haas A, Wickner W. Sequential action of two GTPases to promote vacuole docking and fusion. EMBO J. 2000;19:6713-20 pubmed
    ..Thus, two GTPases sequentially govern vacuole docking and fusion. ..
  7. Nipper R, Siller K, Smith N, Doe C, Prehoda K. Galphai generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts. Proc Natl Acad Sci U S A. 2007;104:14306-11 pubmed
    ..We conclude that Pins has multiple activity states that generate cortical polarity and link it with mitotic spindle orientation. ..
  8. LaGrassa T, Ungermann C. The vacuolar kinase Yck3 maintains organelle fragmentation by regulating the HOPS tethering complex. J Cell Biol. 2005;168:401-14 pubmed
    ..Because Yck3 also promotes efficient vacuole inheritance, we propose that tethering complex phosphorylation is a part of a general, switch-like mechanism for driving changes in organelle architecture. ..
  9. Freisinger T, Klünder B, Johnson J, Müller N, Pichler G, Beck G, et al. Establishment of a robust single axis of cell polarity by coupling multiple positive feedback loops. Nat Commun. 2013;4:1807 pubmed publisher
    ..Our results demonstrate how cells optimize symmetry breaking through coupling between multiple feedback loops. ..
  10. Natochin M, Gasimov K, Artemyev N. Inhibition of GDP/GTP exchange on G alpha subunits by proteins containing G-protein regulatory motifs. Biochemistry. 2001;40:5322-8 pubmed
    ..Our results suggest that GPR proteins are potent GDP dissociation inhibitors for Gialpha-like Galpha subunits in vitro, and in this capacity they may inhibit GPCR/Gi protein signaling in vivo. ..
  11. Vetter I, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294:1299-304 pubmed
    ..Here we will try to define some underlying principles. ..
  12. Scheffzek K, Stephan I, Jensen O, Illenberger D, Gierschik P. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI. Nat Struct Biol. 2000;7:122-6 pubmed
    Rho family-specific guanine nucleotide dissociation inhibitors (RhoGDIs) decrease the rate of nucleotide dissociation and release Rho proteins such as RhoA, Rac and Cdc42 from membranes, forming tight complexes that shuttle between ..
  13. Bielek H, Anselmo A, DerMardirossian C. Morphological and proliferative abnormalities in renal mesangial cells lacking RhoGDI. Cell Signal. 2009;21:1974-83 pubmed publisher
    ..These functional and structural changes are likely to contribute to the defects in renal architecture and function observed in the RhoGDI (-/-) mouse. ..
  14. Bowman S, Neumüller R, Novatchkova M, Du Q, Knoblich J. The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. Dev Cell. 2006;10:731-42 pubmed
    ..Our data suggest a model in which asymmetrically localized Pins-G alphai complexes regulate spindle orientation by directly binding to Mud. ..
  15. DerMardirossian C, Bokoch G. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005;15:356-63 pubmed
    ..We propose that phosphorylation mediated by diverse kinases might provide a means of controlling and coordinating Rho GTPase activation. ..
  16. DerMardirossian C, Schnelzer A, Bokoch G. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell. 2004;15:117-27 pubmed
    ..These results support a role for Pak1-mediated RhoGDI phosphorylation as a mechanism for Cdc42-mediated Rac activation, and suggest the possibility of Rac-induced positive feed-forward regulation of Rac activity. ..
  17. Guilgur L, Prudêncio P, Ferreira T, Pimenta Marques A, Martinho R. Drosophila aPKC is required for mitotic spindle orientation during symmetric division of epithelial cells. Development. 2012;139:503-13 pubmed publisher
  18. Groysman M, Hornstein I, Alcover A, Katzav S. Vav1 and Ly-GDI two regulators of Rho GTPases, function cooperatively as signal transducers in T cell antigen receptor-induced pathways. J Biol Chem. 2002;277:50121-30 pubmed
    ..Thus, our data suggest that the interaction of Vav1 and Ly-GDI creates a fine tuning mechanism for the regulation of intracellular signaling pathways leading to NFAT stimulation. ..
  19. Kimple R, Willard F, Hains M, Jones M, Nweke G, Siderovski D. Guanine nucleotide dissociation inhibitor activity of the triple GoLoco motif protein G18: alanine-to-aspartate mutation restores function to an inactive second GoLoco motif. Biochem J. 2004;378:801-8 pubmed
    ..Galpha(i/o)-Loco' interaction) motif proteins have recently been identified as novel GDIs (guanine nucleotide dissociation inhibitors) for heterotrimeric G-protein alpha subunits...
  20. Das A, Slaughter B, Unruh J, Bradford W, Alexander R, Rubinstein B, et al. Flippase-mediated phospholipid asymmetry promotes fast Cdc42 recycling in dynamic maintenance of cell polarity. Nat Cell Biol. 2012;14:304-10 pubmed publisher
  21. Boulter E, Garcia Mata R, Guilluy C, Dubash A, Rossi G, Brennwald P, et al. Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat Cell Biol. 2010;12:477-83 pubmed publisher
    At steady state, most Rho GTPases are bound in the cytosol to Rho guanine nucleotide dissociation inhibitors (RhoGDIs). RhoGDIs have generally been considered to hold Rho proteins passively in an inactive state within the cytoplasm...
  22. de Vries L, Fischer T, Tronchere H, Brothers G, Strockbine B, Siderovski D, et al. Activator of G protein signaling 3 is a guanine dissociation inhibitor for Galpha i subunits. Proc Natl Acad Sci U S A. 2000;97:14364-9 pubmed
    ..Inhibition of the Galpha subunit and stimulation of heterotrimeric G protein signaling, presumably by stimulating Gbetagamma, extend the possibilities for modulating signal transduction through heterotrimeric G proteins. ..
  23. Pfeffer S. Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol. 2001;11:487-91 pubmed
    ..Rabs organize distinct protein scaffolds within a single organelle and act in a combinatorial manner with their effectors to regulate all stages of membrane traffic. ..
  24. Johnson J, Erickson J, Cerione R. New insights into how the Rho guanine nucleotide dissociation inhibitor regulates the interaction of Cdc42 with membranes. J Biol Chem. 2009;284:23860-71 pubmed publisher
  25. Cavalli V, Vilbois F, Corti M, Marcote M, Tamura K, Karin M, et al. The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. Mol Cell. 2001;7:421-32 pubmed
    ..Our observations reveal the existence of a cross-talk between endocytosis and the p38-dependent stress response, thus providing molecular evidence that endocytosis can be regulated by the environment. ..
  26. Ho T, Merajver S, Lapiere C, Nusgens B, Deroanne C. RhoA-GDP regulates RhoB protein stability. Potential involvement of RhoGDIalpha. J Biol Chem. 2008;283:21588-98 pubmed publisher
    ..Our results highlight RhoGDIalpha-dependent cross-talks that regulate the stability of RhoGTPases. ..
  27. Mehta D, Rahman A, Malik A. Protein kinase C-alpha signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. J Biol Chem. 2001;276:22614-20 pubmed
    ..Taken together, these results indicate that PKC-alpha is critical in regulating GDI phosphorylation, Rho activation, and in signaling Rho-dependent endothelial barrier dysfunction. ..
  28. Wang Z, Thurmond D. Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion. J Biol Chem. 2010;285:6186-97 pubmed publisher
  29. Hoffman G, Nassar N, Cerione R. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell. 2000;100:345-56 pubmed
    ..The structural data demonstrate how GDIs serve as negative regulators of small GTP-binding proteins and how the isoprenoid moiety is utilized in this critical regulatory interaction. ..
  30. Lin Q, Fuji R, Yang W, Cerione R. RhoGDI is required for Cdc42-mediated cellular transformation. Curr Biol. 2003;13:1469-79 pubmed
    ..Taken together, the results reported here indicate that despite being a negative regulator of Cdc42 activation and GTP hydrolysis, RhoGDI plays an essential role in Cdc42-mediated cellular transformation. ..
  31. Elfenbein A, Rhodes J, Meller J, Schwartz M, Matsuda M, Simons M. Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway. J Cell Biol. 2009;186:75-83 pubmed publisher
    ..Thus, FGF2-induced Rac1 activation depends on the suppression of RhoG by a previously uncharacterized ternary S4-synectin-RhoGDI1 protein complex and activation via PKCalpha. ..
  32. Afshar K, Willard F, Colombo K, Siderovski D, GONCZY P. Cortical localization of the Galpha protein GPA-16 requires RIC-8 function during C. elegans asymmetric cell division. Development. 2005;132:4449-59 pubmed
  33. Zhang B, Zhang Y, Dagher M, Shacter E. Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 2005;65:6054-62 pubmed
    ..Taken together, the data show that RhoGDI is an anti-apoptotic molecule that mediates cellular resistance to these chemotherapy agents. ..
  34. Willard F, Kimple R, Siderovski D. Return of the GDI: the GoLoco motif in cell division. Annu Rev Biochem. 2004;73:925-51 pubmed
    ..We discuss potential mechanisms by which GoLoco/Galpha complexes might modulate spindle dynamics. ..
  35. Zhang B. Rho GDP dissociation inhibitors as potential targets for anticancer treatment. Drug Resist Updat. 2006;9:134-41 pubmed
    ..This review will discuss the dual roles of RhoGDIs in the regulation of Rho GTPases, highlighting a possible role in regulating tumorigenicity. In addition, the potential for targeting RhoGDIs for anticancer therapy will be discussed. ..
  36. Wang L, Li G, Sugita S. RalA-exocyst interaction mediates GTP-dependent exocytosis. J Biol Chem. 2004;279:19875-81 pubmed
    ..Furthermore, GTP- and Ca2+-dependent exocytosis use different sensors and effectors for triggering exocytosis whereas their final fusion steps are both SNARE-dependent. ..
  37. Golovanov A, Hawkins D, Barsukov I, Badii R, Bokoch G, Lian L, et al. Structural consequences of site-directed mutagenesis in flexible protein domains: NMR characterization of the L(55,56)S mutant of RhoGDI. Eur J Biochem. 2001;268:2253-60 pubmed
    ..The origins of the effect of the L55S/L56S mutation on the binding constant (decreased by at least three orders of magnitude relative to wild-type) are discussed with particular reference to the flexibility of this part of the protein. ..
  38. Ugolev Y, Berdichevsky Y, Weinbaum C, Pick E. Dissociation of Rac1(GDP).RhoGDI complexes by the cooperative action of anionic liposomes containing phosphatidylinositol 3,4,5-trisphosphate, Rac guanine nucleotide exchange factor, and GTP. J Biol Chem. 2008;283:22257-71 pubmed publisher
    ..RhoGDI complexes, p67(phox), GTP, and Rac GEF constructs with affinity for PtdIns(3,4,5)P(3) at a level superior to that of native membranes. ..
  39. Cho H, Baek K, Park S, Kim I, Choi Y, Cho H, et al. RhoGDI2 expression is associated with tumor growth and malignant progression of gastric cancer. Clin Cancer Res. 2009;15:2612-9 pubmed publisher
    ..Our findings indicate that RhoGDI2 is involved in gastric tumor growth and metastasis, and that RhoGDI2 may be a useful marker for tumor progression of human gastric cancer. ..
  40. D Adamo P, Welzl H, Papadimitriou S, Raffaele di Barletta M, Tiveron C, Tatangelo L, et al. Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet. 2002;11:2567-80 pubmed
    ..The general similarity to human mental retardation is striking, and suggests that the Gdi1 mutants may provide insights into the human defect and into the molecular mechanisms important for development of cognitive functions. ..
  41. Harding M, Theodorescu D. RhoGDI2: a new metastasis suppressor gene: discovery and clinical translation. Urol Oncol. 2007;25:401-6 pubmed
    ..These targets, endothelin-1 and Neuromedin U are excellent potential targets for therapeutic intervention in the metastatic cascade. ..
  42. Sheffield P, Garrard S, Derewenda Z. Overcoming expression and purification problems of RhoGDI using a family of "parallel" expression vectors. Protein Expr Purif. 1999;15:34-9 pubmed
  43. Ota T, Maeda M, Suto S, Tatsuka M. LyGDI functions in cancer metastasis by anchoring Rho proteins to the cell membrane. Mol Carcinog. 2004;39:206-20 pubmed
    ..These results suggest that LyGDI functions in the cell membrane to afford spatial regulation of Rho family GTPase signaling through ezrin radixin moesin (ERM) proteins during metastasis. ..
  44. Richman T, Toenjes K, Morales S, Cole K, Wasserman B, Taylor C, et al. Analysis of cell-cycle specific localization of the Rdi1p RhoGDI and the structural determinants required for Cdc42p membrane localization and clustering at sites of polarized growth. Curr Genet. 2004;45:339-49 pubmed
    ..Taken together, these results provide insight into the complicated nature of the relationships between Cdc42p localization, nucleotide binding, and protein-protein interactions. ..
  45. Michaelson D, Silletti J, Murphy G, D EUSTACHIO P, Rush M, Philips M. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J Cell Biol. 2001;152:111-26 pubmed
    ..Thus, despite the common essential feature of the CAAX (prenylation, AAX tripeptide proteolysis, and carboxyl methylation) motif, the subcellular localizations of Rho GTPases, like their functions, are diverse and dynamic. ..
  46. Suh H, Lee D, Lee K, Ku B, Choi S, Woo J, et al. Structural insights into the dual nucleotide exchange and GDI displacement activity of SidM/DrrA. EMBO J. 2010;29:496-504 pubmed publisher
    ..In comparison with an eukaryotic GEF TRAPP I, this bacterial GEF/GDF exhibits high binding affinity for Rab1 with GDP retained at the active site, which appears as the key feature for the GDF activity of the protein. ..
  47. Dransart E, Olofsson B, Cherfils J. RhoGDIs revisited: novel roles in Rho regulation. Traffic. 2005;6:957-66 pubmed
    ..factors and GTPase-activating proteins, to a cytosol/membrane cycle, regulated by guanine nucleotide dissociation inhibitors (rhoGDIs)...
  48. Groves B, Gong Q, Xu Z, Huntsman C, Nguyen C, Li D, et al. A specific role of AGS3 in the surface expression of plasma membrane proteins. Proc Natl Acad Sci U S A. 2007;104:18103-8 pubmed
    ..Taken together, our data support a model wherein AGS3 modulates the protein trafficking along the TGN/plasma membrane/endosome loop. ..
  49. Gibson R, Wilson Delfosse A. RhoGDI-binding-defective mutant of Cdc42Hs targets to membranes and activates filopodia formation but does not cycle with the cytosol of mammalian cells. Biochem J. 2001;359:285-94 pubmed
    ..However, it does seem that redistribution of Cdc42Hs to the cytosolic compartment is absolutely dependent on RhoGDI interaction. ..
  50. Brunet N, Morin A, Olofsson B. RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain. Traffic. 2002;3:342-57 pubmed
    b>Guanine nucleotide dissociation inhibitors (GDIs) regulate both GDP/GTP and membrane association/dissociation cycles of Rho/Rac and Rab proteins...
  51. Zhou X, Suto S, Ota T, Tatsuka M. Nuclear translocation of cleaved LyGDI dissociated from Rho and Rac during Trp53-dependent ionizing radiation-induced apoptosis of thymus cells in vitro. Radiat Res. 2004;162:287-95 pubmed
  52. Dovas A, Couchman J. RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J. 2005;390:1-9 pubmed
    ..All these results point to a wider role for RhoGDI than initially perceived, making it a binding partner that can tightly control Rho GTPases, but which also allows them to reach their full spectrum of activities. ..
  53. Genth H, Gerhard R, Maeda A, Amano M, Kaibuchi K, Aktories K, et al. Entrapment of Rho ADP-ribosylated by Clostridium botulinum C3 exoenzyme in the Rho-guanine nucleotide dissociation inhibitor-1 complex. J Biol Chem. 2003;278:28523-7 pubmed
    ..The increased stability of the GDI complex prevented binding of Rho to membrane-associated players of the GTPase cycle such as the activating guanine nucleotide exchange factors and effector proteins. ..