title: Tiam1-IRSp53 complex formation directs specificity of rac-mediated actin cytoskeleton regulation.
abstract: The exchange factor Tiam1 regulates multiple cellular functions by activating the Rac GTPase. Active Rac has various effects in cells, including alteration of actin cytoskeleton and gene expression, via binding to and modulating the activity of diverse effector proteins. How individual Rac effectors are selected for activation and regulated in response to upstream signals is not well understood. We find that Tiam1 contributes to both of these processes by binding to IRSp53, an adaptor protein that is an effector for both Rac and Cdc42. Tiam1 directs IRSp53 to Rac signaling by enhancing IRSp53 binding to both active Rac and the WAVE2 scaffold. Moreover, Tiam1 promotes IRSp53 localization to Rac-induced lamellipodia rather than Cdc42-induced filopodia. Finally, IRSp53 depletion from cells prevents Tiam1-dependent lamellipodia induced by Tiam1 overexpression or platelet-derived growth factor stimulation. These findings indicate that Tiam1 not only activates Rac but also contributes to Rac signaling specificity through binding to IRSp53.
authors.affiliation: The Department of Biochemistry, Tufts University School of Medicine, Tufts-New England Medical Center, Boston, MA 02111, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Connolly
authors.forename: Jared
authors.initials: J
authors.lastname: Rice
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Buchsbaum
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020798:Two-Hybrid System Techniques; D051300:Wiskott-Aldrich Syndrome Protein Family; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C119539:BAIAP2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; C513259:Tiam1 protein, rat; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins