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J. Biol. Chem., Vol. 281, Issue 24, 16482-16492, June 16, 2006

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Protein-tyrosine Phosphatase (PTP) Wedge Domain Peptides

A NOVEL APPROACH FOR INHIBITION OF PTP FUNCTION AND AUGMENTATION OF PROTEIN-TYROSINE KINASE FUNCTION^*

Youmei Xie, Stephen M. Massa^¶, Sonya E. Ensslen-Craig^||, Denice L. Major^||, Tao Yang, Michelle A. Tisi, Vicki D. Derevyanny, William O. Runge, Brijesh P. Mehta, Laura A. Moore, Susann M. Brady-Kalnay^¶1, and Frank M. Longo²

From the Department of Neurology, University of North Carolina, Chapel Hill, North Carolina 27599, Department of Neurology and ^¶Laboratory for Computational Neurochemistry and Drug Discovery, San Francisco Veterans Affairs Medical Center and Dept. of Neurology, University of California, San Francisco, San Francisco, California 94121, and ^||Departments of Neurosciences and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio 44106

Inhibition of protein-tyrosine phosphatases (PTPs) counterbalancing protein-tyrosine kinases (PTKs) offers a strategy for augmenting PTK actions. Conservation of PTP catalytic sites limits development of specific PTP inhibitors. A number of receptor PTPs, including the leukocyte common antigen-related (LAR) receptor and PTPµ, contain a wedge-shaped helix-loop-helix located near the first catalytic domain. Helix-loop-helix domains in other proteins demonstrate homophilic binding and inhibit function; therefore, we tested the hypothesis that LAR wedge domain peptides would exhibit homophilic binding, bind to LAR, and inhibit LAR function. Fluorescent beads coated with LAR or PTPµ wedge peptides demonstrated PTP-specific homophilic binding, and LAR wedge peptide-coated beads precipitated LAR protein. Administration of LAR wedge Tat peptide to PC12 cells resulted in increased proliferation, decreased cell death, increased neurite outgrowth, and augmented Trk PTK-mediated responses to nerve growth factor (NGF), a phenotype matching that found in PC12 cells with reduced LAR levels. PTPµ wedge Tat peptide had no effect on PC12 cells but blocked the PTPµ-dependent phenotype of neurite outgrowth of retinal ganglion neurons on a PTPµ substrate, whereas LAR wedge peptide had no effect. The survival- and neurite-promoting effect of the LAR wedge peptide was blocked by the Trk inhibitor K252a, and reciprocal co-immunoprecipitation demonstrated LAR/TrkA association. The addition of LAR wedge peptide inhibited LAR co-immunoprecipitation with TrkA, augmented NGF-induced activation of TrkA, ERK, and AKT, and in the absence of exogenous NGF, induced activation of TrkA, ERK, and AKT. PTP wedge domain peptides provide a unique PTP inhibition strategy and offer a novel approach for augmenting PTK function.

Received for publication, April 3, 2006

^* This research was supported in part by National Institutes of Health Grants R01-AG09873 (to F. M. L.) and R01-EY12251 (to S. B.-K.) and by the Veterans Administration (to F. M. L. and S. M. M.). 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 Supported by NEI, National Institutes of Health Core Grant PO-EY11373 (to the Visual Sciences Research Center of Case Western Reserve University).

² To whom correspondence should be addressed: Dept. of Neurology and Neurological Sciences, Stanford University, 300 Pasteur Dr., Stanford, CA 94305. Tel.: 650-725-6673; Fax: 650-498-4579; E-mail: longo{at}stanford.edu.

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