HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 50, 47530-47541, December 14, 2001

This Article Full Text Full Text (PDF) An addition or correction has been published All Versions of this Article: 276/50/47530    most recent M108865200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gao, Y. Articles by Zheng, Y. Search for Related Content PubMed PubMed Citation Articles by Gao, Y. Articles by Zheng, Y. Social Bookmarking                      What's this?

Trp⁵⁶ of Rac1 Specifies Interaction with a Subset of Guanine Nucleotide Exchange Factors^*

Yuan Gao, Jingchuan Xing, Michel Streuli^§, Thomas L. Leto^¶, and Yi Zheng

From the  Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the ^§ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and ^¶ Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892

Signaling specificity of Rho GTPase pathways is achieved in part by selective interaction between members of the Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. For example, Trio, GEF-H1, and Tiam1 are a subset of GEFs that specifically activate Rac1 but not the closely related Cdc42. The Rac1 specificity of these GEFs appears to be governed by Rac1-GEF binding interaction. To understand the detailed mechanism underlying the GEF specificity issue, we have analyzed a panel of chimeras made between Rac1 and Cdc42 and examined a series of point mutants of Rac1 made at the switch I, switch II, and ₂/₃ regions for their ability to interact with and to be activated by the GEFs. The results reveal that Rac1 residues of both the switch I and switch II regions are involved in GEF docking and GEF-mediated nucleotide disruption, because mutation of Asp³⁸, Asn³⁹, Gln⁶¹, Tyr⁶⁴, or Arg⁶⁶/Leu⁶⁷ into Ala results in the loss of GEF binding, whereas mutation at Tyr³², Asp⁶⁵, or Leu⁷⁰/Ser⁷¹ leads to the loss of GEF catalysis while retaining the binding capability. The region between amino acids 53-72 of Rac1 is required for specific recognition and activation by the GEFs, and Trp⁵⁶ in ₃ appears to be the critical determinant. Introduction of Trp⁵⁶ to Cdc42 renders it fully responsive to the Rac-specific GEF in vitro and in cells. Further, a polypeptide derived from the ₃ region of Rac1 including the Trp⁵⁶ residue serves as a specific inhibitor for Rac1 interaction with the GEFs. Taken together, these results indicate that Trp⁵⁶ is the necessary and sufficient determinant of Rac1 for discrimination by the subset of Rac1-specific GEFs and suggest that a compound mimicking Trp⁵⁶ action could be explored as an interfering reagent specifically targeting Rac1 activation.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				H. Hope, S. Bogliolo, R. A. Arkowitz, and M. Bassilana Activation of Rac1 by the Guanine Nucleotide Exchange Factor Dck1 Is Required for Invasive Filamentous Growth in the Pathogen Candida albicans Mol. Biol. Cell, September 1, 2008; 19(9): 3638 - 3651. [Abstract] [Full Text] [PDF]

				Y. Ugolev, Y. Berdichevsky, C. Weinbaum, and E. Pick Dissociation of Rac1(GDP){middle dot}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., August 8, 2008; 283(32): 22257 - 22271. [Abstract] [Full Text] [PDF]

				M. A. Kwofie and J. Skowronski Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors J. Biol. Chem., February 8, 2008; 283(6): 3088 - 3096. [Abstract] [Full Text] [PDF]

				S. E. Siegrist and C. Q. Doe Microtubule-induced cortical cell polarity Genes & Dev., March 1, 2007; 21(5): 483 - 496. [Abstract] [Full Text] [PDF]

				K.-W. Wong, S. Mohammadi, and R. R. Isberg Disruption of RhoGDI and RhoA Regulation by a Rac1 Specificity Switch Mutant J. Biol. Chem., December 29, 2006; 281(52): 40379 - 40388. [Abstract] [Full Text] [PDF]

				A. Oleksy, L/u. Opalinski, U. Derewenda, Z. S. Derewenda, and J. Otlewski The Molecular Basis of RhoA Specificity in the Guanine Nucleotide Exchange Factor PDZ-RhoGEF J. Biol. Chem., October 27, 2006; 281(43): 32891 - 32897. [Abstract] [Full Text] [PDF]

				M. Bassilana and R. A. Arkowitz Rac1 and Cdc42 Have Different Roles in Candida albicans Development Eukaryot. Cell, February 1, 2006; 5(2): 321 - 329. [Abstract] [Full Text] [PDF]

				C. J. Bakal, D. Finan, J. LaRose, C. D. Wells, G. Gish, S. Kulkarni, P. DeSepulveda, A. Wilde, and R. Rottapel The Rho GTP exchange factor Lfc promotes spindle assembly in early mitosis PNAS, July 5, 2005; 102(27): 9529 - 9534. [Abstract] [Full Text] [PDF]

				M. G. Callow, S. Zozulya, M. L. Gishizky, B. Jallal, and T. Smeal PAK4 mediates morphological changes through the regulation of GEF-H1 J. Cell Sci., May 1, 2005; 118(9): 1861 - 1872. [Abstract] [Full Text] [PDF]

				A. Mizrahi, S. Molshanski-Mor, C. Weinbaum, Y. Zheng, M. Hirshberg, and E. Pick Activation of the Phagocyte NADPH Oxidase by Rac Guanine Nucleotide Exchange Factors in Conjunction with ATP and Nucleoside Diphosphate Kinase J. Biol. Chem., February 4, 2005; 280(5): 3802 - 3811. [Abstract] [Full Text] [PDF]

				K. R. Skowronek, F. Guo, Y. Zheng, and N. Nassar The C-terminal Basic Tail of RhoG Assists the Guanine Nucleotide Exchange Factor Trio in Binding to Phospholipids J. Biol. Chem., September 3, 2004; 279(36): 37895 - 37907. [Abstract] [Full Text] [PDF]

				Y. Gao, J. B. Dickerson, F. Guo, J. Zheng, and Y. Zheng Rational design and characterization of a Rac GTPase-specific small molecule inhibitor PNAS, May 18, 2004; 101(20): 7618 - 7623. [Abstract] [Full Text] [PDF]

				J.-F. Cote and K. Vuori Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity J. Cell Sci., March 14, 2003; 115(24): 4901 - 4913. [Abstract] [Full Text] [PDF]

				K. Robbe, A. Otto-Bruc, P. Chardin, and B. Antonny 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., February 7, 2003; 278(7): 4756 - 4762. [Abstract] [Full Text] [PDF]

				N. Sigal, Y. Gorzalczany, R. Sarfstein, C. Weinbaum, Y. Zheng, and E. Pick The Guanine Nucleotide Exchange Factor Trio Activates the Phagocyte NADPH Oxidase in the Absence of GDP to GTP Exchange on Rac. "THE EMPEROR'S NEW CLOTHES" J. Biol. Chem., February 7, 2003; 278(7): 4854 - 4861. [Abstract] [Full Text] [PDF]

				L. Cheng, K. L. Rossman, G. M. Mahon, D. K. Worthylake, M. Korus, J. Sondek, and I. P. Whitehead RhoGEF Specificity Mutants Implicate RhoA as a Target for Dbs Transforming Activity Mol. Cell. Biol., October 1, 2002; 22(19): 6895 - 6905. [Abstract] [Full Text] [PDF]