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J. Biol. Chem., Vol. 280, Issue 22, 20995-21003, June 3, 2005

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Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells^*

Meghan E. McMullen, Patrick W. Bryant, Christopher C. Glembotski, Peter A. Vincent¶, and Kevin M. Pumiglia||

From the Centers for Cell Biology and Cancer Research and ^¶Cardiovascular Sciences, Albany Medical College, Albany, New York 12208 and the San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, California 92182

Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.

Received for publication, June 23, 2004 , and in revised form, March 23, 2005.

^* This work was supported by NCI, National Institutes of Health Public Health Service Grants R01-CA-81419 and CA-90653 (to K. M. P.), National Institutes of Health Grants HL075573 and NS/HL 20537 (to C. C. G.), funds from the David E. Bryant Trust (to K. M. P.), and National Institutes of Health Predoctoral Training Grant T32-HL-07194 (to 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 (showing that MKP-1 inhibition raises phospho-p38 levels without inhibiting dephosphorylation) and 2 (showing that sustained p38 activation does not inhibit stress fiber formation in adherent endothelial cells).

^|| To whom correspondence should be addressed: Center for Cell Biology and Cancer Research, 47 New Scotland Ave., MC-165, Albany, NY 12208; Tel.: 518-262-6587; Fax: 518-262-5669; E-mail: pumiglk{at}mail.amc.edu.

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