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J. Biol. Chem., Vol. 278, Issue 52, 52587-52597, December 26, 2003

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PEA-15 Binding to ERK1/2 MAPKs Is Required for Its Modulation of Integrin Activation^*

From the ^aDepartment of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, ^dLaboratory of Molecular Biophysics, The Rockefeller University, New York, New York 10021, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, the ^gInstitute of Signaling, Developmental Biology, and Cancer Research, CNRS UMR 6543, 06189 Nice, France, and the ^hInstitute of Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck 6020, Austria

Activation of Raf-1 suppresses integrin activation, potentially through the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). However, bulk ERK1/2 activation does not correlate with suppression. PEA-15 reverses suppression of integrin activation and binds ERK1/2. Here we report that PEA-15 reversal of integrin suppression depends on its capacity to bind ERK1/2, indicating that ERK1/2 function is indeed required for suppression. Mutations in either the death effector domain or C-terminal tail of PEA-15 that block ERK1/2 binding abrogated the reversal of integrin suppression. Furthermore, we used ERK/p38 chimeras and site-directed mutagenesis to identify ERK1/2 residues required for binding PEA-15. Mutations of residues that precede the G helix and within the mitogen-activated protein kinase insert blocked ERK2 binding to PEA-15, but not activation of ERK2. These ERK2 mutants blocked the ability of PEA-15 to reverse suppression of integrin activation. Thus, PEA-15 regulation of integrin activation depends on its binding to ERK1/2. To directly test the role of ERK1/2 localization in suppression, we enforced membrane association of ERK1 and 2 by joining a membrane-targeting CAAX box sequence to them. Both ERK1-CAAX and ERK2-CAAX were membrane-localized and suppressed integrin activation. In contrast to suppression by membrane-targeted Raf-CAAX, suppression by ERK1/2-CAAX was not reversed by PEA-15. Thus, ERK1/2 are the Raf effectors for suppression of integrin activation, and PEA-15 reverses suppression by binding ERK1/2.

Received for publication, August 22, 2003

^* This work was supported by National Institutes of Health (NIH) Grants CA93849-01 (to J. W. R.), HL-57900 and HL-48728 (to M. H. G.), National Science Foundation Grant MCB-0095074, NIH Grant GM-60614, and a career development award from the Irma T. Hirschl Trust (to M. H. W.). This is publication number 15465-CB from the Scripps Research Institute. 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.

^b Recipient of a postdoctoral fellowship from the American Heart Association.

^c These two authors contributed equally to this work.

^e Present address: Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia.

^f Recipient of postdoctoral fellowships from the Human Frontier Science Program (LT0537), the NHMRC of Australia (997045), and the Norman and Rosita Winston Foundation.

^j A Distinguished Young Scholar of the W. M. Keck Foundation. To whom correspondence may be addressed: Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Ave., Box 42, New York, NY 10021. Fax: 212-327-7222; E-mail: mwerner{at}portugal.rockefeller.edu. ^k To whom correspondence may be addressed: The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Fax: 858-784-7343; E-mail: ginsberg{at}scripps.edu.

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