title: Positive regulation of Rho GTPase activity by RhoGDIs as a result of their direct interaction with GAPs.
abstract: BACKGROUND
  Rho GTPases function as molecular switches in many different signaling pathways and control a wide range of cellular processes. Rho GDP-dissociation inhibitors (RhoGDIs) regulate Rho GTPase signaling and can function as both negative and positive regulators. The role of RhoGDIs as negative regulators of Rho GTPase signaling has been extensively investigated; however, little is known about how RhoGDIs act as positive regulators. Furthermore, it is unclear how this opposing role of GDIs influences the Rho GTPase cycle. We constructed ordinary differential equation models of the Rho GTPase cycle in which RhoGDIs inhibit the regulatory activities of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) by interacting with them directly as well as by sequestering the Rho GTPases. Using this model, we analyzed the role of RhoGDIs in Rho GTPase signaling.
  
  
  RESULTS
  The model constructed in this study showed that the functions of GEFs and GAPs are integrated into Rho GTPase signaling through the interactions of these regulators with GDIs, and that the negative role of GDIs is to suppress the overall Rho activity by inhibiting GEFs. Furthermore, the positive role of GDIs is to sustain Rho activation by inhibiting GAPs under certain conditions. The interconversion between transient and sustained Rho activation occurs mainly through changes in the affinities of GDIs to GAPs and the concentrations of GAPs.
  
  
  CONCLUSIONS
  RhoGDIs positively regulate Rho GTPase signaling primarily by interacting with GAPs and may participate in the switching between transient and sustained signals of the Rho GTPases. These findings enhance our understanding of the physiological roles of RhoGDIs and Rho GTPase signaling.
authors: Division of Tumor Biology, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan. takahide@kanazawa-med.ac.jp.
authors: Takahide
authors: T
authors: Ota
authors: Masayo
authors: M
authors: Maeda
authors: Mayumi
authors: M
authors: Okamoto
authors: Masaaki
authors: M
authors: Tatsuka
mesh_terms: D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020741:rho GTP-Binding Proteins
references: Mol Carcinog. 2004 Apr;39(4):206-20
references: 15057873
references: Clin Cancer Res. 2004 Jun 1;10(11):3800-6
references: 15173088
references: Mol Cell. 2004 Jul 2;15(1):117-27
references: 15225553
references: J Biol Chem. 1990 Jun 5;265(16):9373-80
references: 2111820
references: J Pharm Sci. 1991 Dec;80(12):1141-6
references: 1815072
references: Science. 1992 Oct 30;258(5083):812-5
references: 1439791
references: J Biol Chem. 1993 Jan 15;268(2):775-8
references: 8419353
references: Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1479-83
references: 8434008
references: EMBO J. 1993 May;12(5):1915-21
references: 8491184
references: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7568-72
references: 8356058
references: J Biol Chem. 1993 Nov 15;268(32):23959-63
references: 8226937
references: J Biol Chem. 1993 Dec 15;268(35):26206-11
references: 8253741
references: Exp Cell Res. 1993 Dec;209(2):165-74
references: 8262133
references: Cell. 1995 Jan 27;80(2):179-85
references: 7834738
references: J Biol Chem. 1996 Apr 26;271(17):10004-9
references: 8626553
references: Oncogene. 1997 Jul 24;15(4):417-22
references: 9242378
references: Biochem Biophys Res Commun. 1998 Apr 28;245(3):641-5
references: 9588168
references: EMBO J. 1998 Nov 16;17(22):6608-21
references: 9822605
references: Eur J Cell Biol. 1999 Aug;78(8):539-48
references: 10494860
references: Nature. 2005 May 26;435(7041):513-8
references: 15864301
references: Trends Cell Biol. 2005 Jul;15(7):356-63
references: 15921909
references: Nat Biotechnol. 2005 Aug;23(8):961-6
references: 16082367
references: Biochem J. 2005 Aug 15;390(Pt 1):1-9
references: 16083425
references: Traffic. 2005 Nov;6(11):957-66
references: 16190977
references: Mol Biol Cell. 2006 Nov;17(11):4760-8
references: 16943322
references: Nat Cell Biol. 2006 Nov;8(11):1195-203
references: 17060902
references: Cell Biol Int. 2007 Jan;31(1):92-6
references: 17049467
references: Clin Exp Metastasis. 2006;23(7-8):323-34
references: 17111235
references: J Cell Biol. 2007 Jun 4;177(5):817-27
references: 17535963
references: PLoS Comput Biol. 2006 Dec 1;2(12):e172
references: 17140284
references: Mol Cell Biol. 2007 Sep;27(18):6323-33
references: 17636025
references: J Biol Chem. 2008 Feb 8;283(6):3023-30
references: 18070886
references: FEBS Lett. 2008 Apr 30;582(10):1437-43
references: 18381072
references: Mol Biol Cell. 2008 Jul;19(7):2885-96
references: 18417612
references: Biochem Biophys Res Commun. 2009 Feb 6;379(2):384-9
references: 19103160
references: J Cell Biol. 2009 Jul 13;186(1):75-83
references: 19581409
references: Cancer Sci. 2009 Sep;100(9):1675-9
references: 19555392
references: J Biol Chem. 2009 Aug 28;284(35):23860-71
references: 19581296
references: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1247-52
references: 20080566
references: Mol Cell Biol. 2010 Jul;30(13):3233-48
references: 20439493
references: J Biol Chem. 2010 Jul 23;285(30):23296-308
references: 20472934
references: Curr Opin Genet Dev. 2010 Dec;20(6):684-93
references: 20956081
references: Nat Rev Mol Cell Biol. 2011 Aug;12(8):493-504
references: 21779026
references: J Biol Chem. 2012 Aug 3;287(32):26549-62
references: 22628549
references: Cancer Metastasis Rev. 2012 Dec;31(3-4):519-28
references: 22718398
references: Int J Oncol. 2013 Feb;42(2):460-8
references: 23232495
references: PLoS Comput Biol. 2013;9(1):e1002831
references: 23326220
references: Biochem Biophys Res Commun. 2013 Mar 29;433(1):1-5
references: 23454383
references: Science. 2003 Oct 24;302(5645):646-50
references: 14576435
references: FEBS Lett. 2000 Feb 4;467(1):75-80
references: 10664460
references: J Biol Chem. 2000 Apr 7;275(14):10141-9
references: 10744696
references: J Biol Chem. 2000 Aug 18;275(33):25299-307
references: 10843989
references: J Cell Biol. 2001 Jan 8;152(1):111-26
references: 11149925
references: J Biol Chem. 2002 Apr 26;277(17):15076-84
references: 11786539
references: Nature. 2002 Dec 12;420(6916):629-35
references: 12478284