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J. Biol. Chem., Vol. 283, Issue 19, 12862-12869, May 9, 2008

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Protein Phosphatase 2A Negatively Regulates Integrin _IIbβ₃ Signaling^*

From the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Integrin _IIbβ₃ activation is critical for platelet physiology and is controlled by signal transduction through kinases and phosphatases. Compared with kinases, a role for phosphatases in platelet integrin _IIbβ₃ signaling is less understood. We report that the catalytic subunit of protein phosphatase 2A (PP2Ac) associates constitutively with the integrin _IIbβ₃ in resting platelets and in human embryonal kidney 293 cells expressing _IIbβ₃. The membrane proximal KVGFFKR sequence within the cytoplasmic domain of integrin _IIb is sufficient to support a direct interaction with PP2Ac. Fibrinogen binding to _IIbβ₃ during platelet adhesion decreased integrin-associated PP2A activity and increased the phosphorylation of a PP2A substrate, vasodilator associated phosphoprotein. Overexpression of PP2Ac in 293 cells decreased _IIbβ₃-mediated adhesion to immobilized fibrinogen. Conversely, small interference RNA mediated knockdown of endogenous PP2Ac expression in 293 cells, enhanced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and accelerated _IIbβ₃ adhesion to fibrinogen and von Willebrand factor. Inhibition of ERK1/2, but not p38 activation, abolished the increased adhesiveness of PP2Ac -depleted 293 cells to fibrinogen. Furthermore, knockdown of PP2A_c expression in bone marrow-derived murine megakaryocytes increased soluble fibrinogen binding induced by protease-activated receptor 4-activating peptide. These studies demonstrate that PP2Ac can negatively regulate integrin _IIbβ₃ signaling by suppressing the ERK1/2 signaling pathway.

Received for publication, October 25, 2007 , and in revised form, February 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL081613 and 0435017N. This work was also supported by the American Heart Association (to K. V. V.). 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 Scientist Development Grant 0630180N from the American Heart Association.

² Present address: Tacoma Family Medicine, Tacoma, WA 98405.

³ Supported in part by NIH Grant T-32HL072754.

⁴ Supported by Scientist Development Grant 0635155N from the American Heart Association.

⁵ To whom correspondence should be addressed: Thrombosis Research Section, Baylor College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX 77030. Tel.: 713-798-8677; Fax: 713-798-3415; E-mail: vvijayan{at}bcm.tmc.edu.

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