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J. Biol. Chem., Vol. 281, Issue 8, 4903-4910, February 24, 2006

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The Receptor Protein-tyrosine Phosphatase PTPµ Interacts with IQGAP1^*

Polly J. Phillips-Mason, Theresa J. Gates, Denice L. Major, David B. Sacks, and Susann M. Brady-Kalnay¹

From the Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

The receptor protein-tyrosine phosphatase PTPµ is a member of the Ig superfamily of cell adhesion molecules. The extracellular domain of PTPµ contains motifs commonly found in cell adhesion molecules. The intracellular domain of PTPµ contains two conserved catalytic domains, only the membrane-proximal domain has catalytic activity. The unique features of PTPµ make it an attractive molecule to transduce signals upon cell-cell contact. PTPµ has been shown to regulate cadherin-mediated cell adhesion, neurite outgrowth, and axon guidance. Protein kinase C is a component of the PTPµ signaling pathway utilized to regulate these events. To aid in the further characterization of PTPµ signaling pathways, we used a series of GST-PTPµ fusion proteins, including catalytically inactive and substrate trapping mutants, to identify PTPµ-interacting proteins. We identified IQGAP1, a known regulator of the Rho GTPases, Cdc42 and Rac1, as a novel PTPµ-interacting protein. We show that this interaction is due to direct binding. In addition, we demonstrate that amino acid residues 765-958 of PTPµ, which include the juxtamembrane domain and 35 residues of the first phosphatase domain, mediate the binding to IQGAP1. Furthermore, we demonstrate that constitutively active Cdc42, and to a lesser extent Rac1, enhances the interaction of PTPµ and IQGAP1. These data indicate PTPµ may regulate Rho-GTPase-dependent functions of IQGAP1 and suggest that IQGAP1 is a component of the PTPµ signaling pathway. In support of this, we show that a peptide that competes IQGAP1 binding to Rho GTPases blocks PTPµ-mediated neurite outgrowth.

Received for publication, June 13, 2005 , and in revised form, December 22, 2005.

^* This work was supported by National Institutes of Health Grants RO1-EY12251 (to S. M. B.-K.) and RO1-CA93645 (to D. B. S.). Additional support was provided by Visual Sciences Research Core Grant PO-EY11373 from the NEI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology and Microbiology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4960. Tel.: 216-368-0330; Fax: 216-368-3055; E-mail: susann.brady-kalnay{at}case.edu.

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