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PMID: 21779026 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The 'invisible hand': regulation of RHO GTPases by RHOGDIs.

Nature reviews. Molecular cell biology ·Vol. 12 ·No. 8 ·2011-07-22 ·Pages 493-504

Garcia-Mata R, Boulter E, Burridge K

Abstract

The 'invisible hand' is a term originally coined by Adam Smith in The Theory of Moral Sentiments to describe the forces of self-interest, competition and supply and demand that regulate the resources in society. This metaphor continues to be used by economists to describe the self-regulating nature of a market economy. The same metaphor can be used to describe the RHO-specific guanine nucleotide dissociation inhibitor (RHOGDI) family, which operates in the background, as an invisible hand, using similar forces to regulate the RHO GTPase cycle.

MeSH Terms
Animals Evolution, Molecular Guanine Nucleotide Dissociation Inhibitors/chemistry,genetics,metabolism Humans Membrane Microdomains/metabolism Metabolic Networks and Pathways Models, Biological Models, Molecular Molecular Chaperones/metabolism Multiprotein Complexes Neoplasms/metabolism Phosphorylation Phylogeny Protein Interaction Domains and Motifs rho GTP-Binding Proteins/chemistry,metabolism rho Guanine Nucleotide Dissociation Inhibitor alpha rho-Specific Guanine Nucleotide Dissociation Inhibitors
Chemicals
ARHGDIA protein, human Guanine Nucleotide Dissociation Inhibitors Molecular Chaperones Multiprotein Complexes rho Guanine Nucleotide Dissociation Inhibitor alpha rho-Specific Guanine Nucleotide Dissociation Inhibitors rho GTP-Binding Proteins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Garcia-Mata Rafael
Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA. rafaelgm@med.unc.edu
Boulter Etienne
Burridge Keith
References (105)
105 references, click to expand
  1. RhoGDI2: a new metastasis suppressor gene: discovery and clinical translation.
    Urol Oncol. 2007 Sep-Oct;25(5):401-6 PMID: 17826660
  2. New insights into how the Rho guanine nucleotide dissociation inhibitor regulates the interaction of Cdc42 with membranes.
    J Biol Chem. 2009 Aug 28;284(35):23860-71 PMID: 19581296
  3. Proteomics study reveals cross-talk between Rho guanidine nucleotide dissociation inhibitor 1 post-translational modifications in epidermal growth factor stimulated fibroblasts.
    J Proteome Res. 2007 Jul;6(7):2623-30 PMID: 17506542
  4. Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation.
    Biochemistry. 2001 Aug 28;40(34):10007-13 PMID: 11513578
  5. The Rho GDI Rdi1 regulates Rho GTPases by distinct mechanisms.
    Mol Biol Cell. 2008 Jul;19(7):2885-96 PMID: 18417612
  6. Polarization of cell growth in yeast. I. Establishment and maintenance of polarity states.
    J Cell Sci. 2000 Feb;113 ( Pt 3):365-75 PMID: 10639324
  7. Diacylglycerol kinase zeta regulates actin cytoskeleton reorganization through dissociation of Rac1 from RhoGDI.
    Mol Biol Cell. 2009 Apr;20(7):2049-59 PMID: 19211846
  8. Essential role of protein kinase C zeta in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP.
    J Cell Biol. 2007 Mar 26;176(7):1049-60 PMID: 17389234
  9. A novel role for RhoGDI as an inhibitor of GAP proteins.
    EMBO J. 1993 May;12(5):1915-21 PMID: 8491184
  10. Interaction of radixin with Rho small G protein GDP/GTP exchange protein Dbl.
    Oncogene. 1998 Jun 25;16(25):3279-84 PMID: 9681826
  11. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding.
    J Cell Biol. 2001 Jan 8;152(1):111-26 PMID: 11149925
  12. Ly-GDI, a GDP-dissociation inhibitor of the RhoA GTP-binding protein, is expressed preferentially in lymphocytes.
    Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7568-72 PMID: 8356058
  13. RhoA phosphorylation induces Rac1 release from guanine dissociation inhibitor alpha and stimulation of vascular smooth muscle cell migration.
    Mol Cell Biol. 2010 Oct;30(20):4786-96 PMID: 20696841
  14. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.
    Cell. 2001 Oct 5;107(1):27-41 PMID: 11595183
  15. Serine phosphorylation negatively regulates RhoA in vivo.
    J Biol Chem. 2003 May 23;278(21):19023-31 PMID: 12654918
  16. Epidermal growth factor-dependent regulation of Cdc42 is mediated by the Src tyrosine kinase.
    J Biol Chem. 2003 Dec 5;278(49):49293-300 PMID: 14506284
  17. Tissue-specific variations in the expression and regulation of the small GTP-binding protein Rho.
    Biochim Biophys Acta. 1994 Jul 21;1222(3):331-8 PMID: 8038201
  18. Ste20-related kinase SLK phosphorylates Ser188 of RhoA to induce vasodilation in response to angiotensin II Type 2 receptor activation.
    Circ Res. 2008 May 23;102(10):1265-74 PMID: 18420945
  19. Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer.
    Clin Cancer Res. 2004 Jun 1;10(11):3800-6 PMID: 15173088
  20. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI.
    Nat Struct Biol. 2000 Feb;7(2):122-6 PMID: 10655614
  21. Biphasic expression of RhoGDI2 in the progression of breast cancer and its negative relation with lymph node metastasis.
    Oncol Rep. 2007 Jun;17(6):1383-9 PMID: 17487395
  22. 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 Jul 23;285(30):23296-308 PMID: 20472934
  23. RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity.
    Mol Cell. 2009 Dec 25;36(6):1060-72 PMID: 20064470
  24. 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 Aug 8;283(32):22257-71 PMID: 18505730
  25. How RhoGDI binds Rho.
    Acta Crystallogr D Biol Crystallogr. 1999 Sep;55(Pt 9):1503-15 PMID: 10489445
  26. Loss of expression of LyGDI (ARHGDIB), a rho GDP-dissociation inhibitor, in Hodgkin lymphoma.
    Br J Haematol. 2007 Oct;139(2):217-23 PMID: 17897297
  27. RhoGDI signaling provides targets for cancer therapy.
    Eur J Cancer. 2010 May;46(7):1252-9 PMID: 20347589
  28. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI.
    Nat Neurosci. 2003 May;6(5):461-7 PMID: 12692556
  29. 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 Jun 22;276(25):22614-20 PMID: 11309397
  30. Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity.
    FEBS Lett. 1998 Jan 30;422(2):269-73 PMID: 9490022
  31. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase.
    Mol Cell. 2004 Jul 2;15(1):117-27 PMID: 15225553
  32. Signaling network of the Btk family kinases.
    Oncogene. 2000 Nov 20;19(49):5651-61 PMID: 11114746
  33. A novel Cdc42Hs mutant induces cellular transformation.
    Curr Biol. 1997 Oct 1;7(10):794-7 PMID: 9368762
  34. RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain.
    Traffic. 2002 May;3(5):342-57 PMID: 11967128
  35. Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI.
    Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4182-7 PMID: 20160093
  36. Phosphoinositide-dependent activation of Rho A involves partial opening of the RhoA/Rho-GDI complex.
    Eur J Biochem. 1999 Jun;262(3):879-89 PMID: 10411652
  37. Integrins regulate Rac targeting by internalization of membrane domains.
    Science. 2004 Feb 6;303(5659):839-42 PMID: 14764880
  38. Morphological and proliferative abnormalities in renal mesangial cells lacking RhoGDI.
    Cell Signal. 2009 Dec;21(12):1974-83 PMID: 19765647
  39. Defective chemokine-directed lymphocyte migration and development in the absence of Rho guanosine diphosphate-dissociation inhibitors alpha and beta.
    J Immunol. 2006 Dec 15;177(12):8512-21 PMID: 17142749
  40. Phosphorylation of GTP dissociation inhibitor by PKA negatively regulates RhoA.
    Am J Physiol Cell Physiol. 2008 Nov;295(5):C1161-8 PMID: 18768928
  41. Dissociation of GDP dissociation inhibitor and membrane translocation are required for efficient activation of Rac by the Dbl homology-pleckstrin homology region of Tiam.
    J Biol Chem. 2003 Feb 14;278(7):4756-62 PMID: 12471028
  42. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease.
    Nat Med. 2008 Dec;14(12):1370-6 PMID: 19029984
  43. Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1.
    J Biol Chem. 2000 Jan 7;275(1):423-8 PMID: 10617634
  44. Effector proteins exert an important influence on the signaling-active state of the small GTPase Cdc42.
    J Biol Chem. 2008 May 16;283(20):14153-64 PMID: 18348980
  45. An activating mutant of Rac1 that fails to interact with Rho GDP-dissociation inhibitor stimulates membrane ruffling in mammalian cells.
    Biochem J. 2004 Mar 1;378(Pt 2):409-19 PMID: 14629200
  46. Comparative proteomic analysis identifies proteins associated with the development and progression of colorectal carcinoma.
    FEBS J. 2010 Oct;277(20):4195-204 PMID: 20812987
  47. The Fer tyrosine kinase regulates interactions of Rho GDP-Dissociation Inhibitor α with the small GTPase Rac.
    BMC Biochem. 2010 Dec 01;11:48 PMID: 21122136
  48. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
    Lancet. 2005 Feb 19-25;365(9460):671-9 PMID: 15721472
  49. Glucose- and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure beta cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion.
    J Clin Invest. 1996 Jul 15;98(2):540-55 PMID: 8755667
  50. Inhibition of invasion of epithelial cells by Tiam1-Rac signaling.
    Science. 1997 Nov 21;278(5342):1464-6 PMID: 9367959
  51. Caveolin-1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor in pancreatic beta-cells.
    J Biol Chem. 2006 Jul 14;281(28):18961-72 PMID: 16714282
  52. An activating mutant of Cdc42 that fails to interact with Rho GDP-dissociation inhibitor localizes to the plasma membrane and mediates actin reorganization.
    Exp Cell Res. 2004 Dec 10;301(2):211-22 PMID: 15530857
  53. Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer.
    Proteomics. 2002 Jan;2(1):76-84 PMID: 11788994
  54. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI.
    Cell. 2000 Feb 4;100(3):345-56 PMID: 10676816
  55. 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 Oct 15;359(Pt 2):285-94 PMID: 11583574
  56. Rho GTPases: biochemistry and biology.
    Annu Rev Cell Dev Biol. 2005;21:247-69 PMID: 16212495
  57. Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells.
    Nat Cell Biol. 2011 Jun;13(6):660-7 PMID: 21572420
  58. Biologically active lipids are regulators of Rac.GDI complexation.
    J Biol Chem. 1993 Dec 15;268(35):26206-11 PMID: 8253741
  59. Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA.
    Nat Cell Biol. 2010 Apr;12(4):390-9 PMID: 20305651
  60. Rho and Rac take center stage.
    Cell. 2004 Jan 23;116(2):167-79 PMID: 14744429
  61. GDI-1 phosphorylation switch at serine 96 induces RhoA activation and increased endothelial permeability.
    Mol Cell Biol. 2007 Sep;27(18):6323-33 PMID: 17636025
  62. 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 Jul 13;186(1):75-83 PMID: 19581409
  63. GDIs: central regulatory molecules in Rho GTPase activation.
    Trends Cell Biol. 2005 Jul;15(7):356-63 PMID: 15921909
  64. A GDP dissociation inhibitor that serves as a GTPase inhibitor for the Ras-like protein CDC42Hs.
    Science. 1992 Oct 30;258(5083):812-5 PMID: 1439791
  65. Phosphorylation of serine 188 protects RhoA from ubiquitin/proteasome-mediated degradation in vascular smooth muscle cells.
    Circ Res. 2005 Jun 10;96(11):1152-60 PMID: 15890975
  66. Rho GDP dissociation inhibitor 2 suppresses metastasis via unconventional regulation of RhoGTPases.
    Cancer Res. 2009 Apr 1;69(7):2838-44 PMID: 19276387
  67. Serine-71 phosphorylation of Rac1/Cdc42 diminishes the pathogenic effect of Clostridium difficile toxin A.
    Cell Microbiol. 2009 Dec;11(12):1816-26 PMID: 19709124
  68. Dual modes of cdc42 recycling fine-tune polarized morphogenesis.
    Dev Cell. 2009 Dec;17(6):823-35 PMID: 20059952
  69. Characterization of the interaction between RhoGDI and Cdc42Hs using fluorescence spectroscopy.
    J Biol Chem. 1996 Apr 26;271(17):10004-9 PMID: 8626553
  70. Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers.
    Clin Cancer Res. 2003 Dec 15;9(17):6432-40 PMID: 14695145
  71. RhoGDI is required for Cdc42-mediated cellular transformation.
    Curr Biol. 2003 Sep 2;13(17):1469-79 PMID: 12956948
  72. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.
    Nat Cell Biol. 2002 Aug;4(8):574-82 PMID: 12134158
  73. Src phosphorylation of RhoGDI2 regulates its metastasis suppressor function.
    Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5807-12 PMID: 19321744
  74. RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas.
    Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4279-84 PMID: 9113980
  75. The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein.
    J Biol Chem. 1992 Nov 15;267(32):22860-8 PMID: 1429634
  76. The expression of rho proteins decreases with human brain tumor progression: potential tumor markers.
    Clin Exp Metastasis. 2002;19(1):9-15 PMID: 11918088
  77. A bifunctional bacterial protein links GDI displacement to Rab1 activation.
    Science. 2007 Nov 9;318(5852):974-7 PMID: 17947549
  78. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton.
    EMBO J. 1999 Feb 1;18(3):578-85 PMID: 9927417
  79. Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
    Oncogene. 1999 Sep 23;18(39):5373-80 PMID: 10498891
  80. Protein prenylation: more than just glue?
    Curr Opin Cell Biol. 1992 Dec;4(6):1008-16 PMID: 1485954
  81. RhoA function in lamellae formation and migration is regulated by the alpha6beta4 integrin and cAMP metabolism.
    J Cell Biol. 2000 Jan 24;148(2):253-8 PMID: 10648558
  82. 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. 1996 Nov 29;271(48):30366-74 PMID: 8939998
  83. 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. 1993 Feb 15;90(4):1479-83 PMID: 8434008
  84. Expression level, subcellular distribution and rho-GDI binding affinity of merlin in comparison with Ezrin/Radixin/Moesin proteins.
    Oncogene. 1999 Aug 26;18(34):4788-97 PMID: 10490812
  85. cAMP-induced morphological changes are counteracted by the activated RhoA small GTPase and the Rho kinase ROKalpha.
    J Biol Chem. 1998 Aug 28;273(35):22554-62 PMID: 9712882
  86. A single residue can modify target-binding affinity and activity of the functional domain of the Rho-subfamily GDP dissociation inhibitors.
    Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2974-8 PMID: 7708758
  87. Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain.
    J Biol Chem. 2002 Aug 16;277(33):30066-71 PMID: 12023958
  88. Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway.
    J Cell Biol. 1996 Oct;135(1):37-51 PMID: 8858161
  89. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins.
    Cell. 1994 May 20;77(4):537-49 PMID: 7999144
  90. Consensus transcriptome signature of perineural invasion in pancreatic carcinoma.
    Mol Cancer Ther. 2009 Jun;8(6):1494-504 PMID: 19509238
  91. Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1.
    Nature. 2000 Dec 7;408(6813):682-8 PMID: 11130063
  92. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein.
    J Biol Chem. 1997 Sep 12;272(37):23371-5 PMID: 9287351
  93. cAMP-induced AQP2 translocation is associated with RhoA inhibition through RhoA phosphorylation and interaction with RhoGDI.
    J Cell Sci. 2003 Apr 15;116(Pt 8):1519-25 PMID: 12640036
  94. Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes.
    EMBO J. 1996 Feb 1;15(3):510-9 PMID: 8599934
  95. Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1.
    Nat Cell Biol. 2010 May;12(5):477-83 PMID: 20400958
  96. RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation.
    J Biol Chem. 2003 Mar 14;278(11):9472-80 PMID: 12524425
  97. RhoGDI-1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs.
    Circ Res. 2007 Jul 6;101(1):50-8 PMID: 17525371
  98. Overexpression of Rho GDP-dissociation inhibitor alpha is associated with tumor progression and poor prognosis of colorectal cancer.
    J Proteome Res. 2008 Sep;7(9):3994-4003 PMID: 18651761
  99. Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes.
    Biochem J. 2002 Jan 15;361(Pt 2):243-54 PMID: 11772396
  100. Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer.
    Clin Cancer Res. 2006 Apr 15;12(8):2419-26 PMID: 16638847
  101. Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI.
    Nat Cell Biol. 2002 Mar;4(3):232-9 PMID: 11862216
  102. Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling.
    Mol Biol Cell. 2006 Nov;17(11):4760-8 PMID: 16943322
  103. 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.
    J Biol Chem. 1990 Jun 5;265(16):9373-80 PMID: 2111820
  104. Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins.
    Oncogene. 1990 Sep;5(9):1321-8 PMID: 2120668
  105. The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines.
    Clin Exp Metastasis. 2000;18(6):519-25 PMID: 11592309
Article Info
Journal
Nature reviews. Molecular cell biology
Abbr.
Nat Rev Mol Cell Biol
ISSN
1471-0080
DOI
10.1038/nrm3153
Email
rafaelgm@med.unc.edu
Published
2011-07-22
Epub
2011-00-22
Pages
493-504
Language
English
Region
England
NLM ID
100962782
PMCID
PMC3260518
Subset
IM
Grants
NHLBI NIH HHS · HL080166 · United States
NIGMS NIH HHS · R01 GM029860-29A1 · United States
NHLBI NIH HHS · P01 HL080166-05 · United States
NIGMS NIH HHS · R01 GM029860 · United States
NHLBI NIH HHS · P01 HL080166 · United States
NIGMS NIH HHS · GM029860 · United States
External Links
PubMed source DOI: 10.1038/nrm3153 PMC Full Text View journal details
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