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J. Biol. Chem., Vol. 280, Issue 8, 7273-7284, February 25, 2005

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Smooth Muscle Actin Determines Mechanical Force-induced p38 Activation^*

Jiaxu Wang, Jennie Fan, Carol Laschinger, Pamela D. Arora, Andras Kapus¶, Arun Seth, and Christopher A. McCulloch||

From the Canadian Institutes of Health, Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Ontario M5S 3E2, and the ^¶Department of Surgery, Faculty of Medicine, University of Toronto, Ontario M5G 2C4, Canada

The mitogen-activated protein kinase p38 is activated by mechanical force, but the cellular elements that mediate force-induced p38 phosphorylation are not defined. As -smooth muscle actin (SMA) is an actin isoform associated with force generation in fibroblasts, we asked if SMA participates in the activation of p38 by force. Tensile forces (0.65 pN/µm²) generated by magnetic fields were applied to collagen-coated magnetite beads bound to Rat-2 cells. Immunoblotting showed that p38 was the predominant p38 isoform. Analysis of bead-associated proteins demonstrated that SMA enrichment of collagen receptor complexes required the 21 integrin. SMA was present almost entirely as filaments. Swinholide depolymerized SMA filaments and blocked force-induced p38 phosphorylation and force-induced increases of SMA. Knockdown of SMA (70% reduction) using RNA interference did not affect -actin but inhibited force-induced p38 phosphorylation by 50%. Inhibition of Rho kinase blocked SMA filament assembly, force-induced increases of SMA, and force-induced p38 activation. Force application increased SMA content and enhanced the association of phosphorylated p38 with SMA filaments. Blockade of p38 phosphorylation by SB203586 abrogated force-induced increases of SMA. In cells transfected with SMA promoter--galactosidase fusion constructs, co-transfection with constitutively active p38 or MKK6 increased SMA promoter activity by 2.5–3-fold. Dominant negative p38 blocked force-induced activation of the SMA promoter. In SMA negative cells, there was no force-induced p38 phosphorylation. We conclude that force-induced p38 phosphorylation is dependent on an SMA filament-dependent pathway that uses a feed-forward amplification loop to synergize force-induced SMA expression with p38 activation.

Received for publication, September 20, 2004 , and in revised form, December 6, 2004.

^* This work was supported in part by Grant T-4819 from the Ontario Heart and Stroke Foundation and Canadian Institutes of Health Research Major Equipment and Group Grants (to A. S. and C. A. 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.

Supported by an Ontario Heart and Stroke Foundation fellowship and Canadian Institutes of Health Research Cell Signals Strategic training fellowship.

^|| To whom correspondence should be addressed: Rm. 244, Fitzgerald Bldg., University of Toronto, 150 College St., Toronto, Ontario M5S 3E2, Canada. Tel.: 416-978-1258; Fax: 416-978-5956; E-mail: christopher.mcculloch{at}utoronto.ca.

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