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Molecular and Cellular Biology, June 2005, p. 4602-4614, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4602-4614.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Tiam1-IRSp53 Complex Formation Directs Specificity of Rac-Mediated Actin Cytoskeleton Regulation{dagger}

Beth A. Connolly,1,{ddagger} Jared Rice,2,{ddagger} Larry A. Feig,1 and Rachel J. Buchsbaum2,3*

The Department of Biochemistry, Tufts University School of Medicine,1 The Molecular Oncology Research Institute,2 The Division of Hematology/Oncology, Tufts-New England Medical Center, Boston, Massachusetts 021113

Received 16 November 2004/ Returned for modification 20 December 2004/ Accepted 9 February 2005

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.

* Corresponding author. Mailing address: Tufts-New England Medical Center, 750 Washington Street, Box 245, Boston, MA 02111. Phone: (617) 636-9555. Fax: (617) 636-2342. E-mail: rachel.buchsbaum{at}tufts.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, June 2005, p. 4602-4614, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4602-4614.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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