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J. Biol. Chem., Vol. 279, Issue 34, 35573-35582, August 20, 2004

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Fibroblast Growth Factor-2 and Remodeled Type I Collagen Control Membrane Protrusion in Human Vascular Smooth Muscle Cells

BIPHASIC ACTIVATION OF Rac1^*

Euridiky Fera, Caroline O'Neil, Wilfred Lee, Shaohua Li, and J. Geoffrey Pickering¶

From the Robarts Research Institute (Vasscular Biology Group), London Health Sciences Centre, Departments of Medicine (Cardiology), Biochemistry, Medical Biophysics, University of Western Ontario, London, Ontario N6A 5K8, Canada

Plasma membrane protrusion is fundamental to cell motility, but its regulation by the extracellular environment is not well elucidated. We have quantified lamellipodial protrusion dynamics in human vascular smooth muscle cells exposed to fibroblast growth factor 2 (FGF-2) and type I collagen, two distinct ligands presented to vascular cells during arterial remodeling. Video microscopy revealed that FGF-2 stimulated a modest increase in lamellipodial protrusion rate that peaked within 15 min. This response was associated with immediate but transient activation of Rac1 and was inhibited in cells infected with retrovirus containing cDNA encoding dominant-negative Rac1. A 1-h exposure to FGF-2 also set up a second phase of more striking lamellipodial protrusion evident at 24–36 h. This delayed response was most pronounced when cells were on type 1 collagen and was associated with FGF-2-induced expression of collagenase-1 that localized to the edge of protruding lamellipodia. Moreover, late membrane protrusion was inhibited when cells were on collagenase-resistant type I collagen, implicating degraded collagen as a mediator. For cells on collagen, the immediate activation of Rac1 by FGF-2 was followed by a sustained wave of Rac1 activation that was inhibited when cleavage of the collagen triple helix was prevented and also by blockade of _v3 integrin. We conclude that lamellipodial protrusion in smooth muscle cells can be regulated by waves of Rac1 activation, corresponding to the sequential presentation of FGF-2 and remodeled collagen. The findings thus reveal a previously unrecognized level of coordination among extracellular input that enables cells to maintain protrusive activity over prolonged periods.

Received for publication, January 22, 2004 , and in revised form, May 26, 2004.

^* This work was supported by Canadian Institutes of Health Research Grant MT11715 and Heart and Stroke Foundation of Canada Grant T4458. 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 online version of this article (available at http://www.jbc.org) contains QuickTime movies.

Supported by a John D. Schultz Award from the Heart and Stroke Foundation of Ontario.

Supported by a Premier's Research Excellence Award (to J. G. P.).

^¶ Career Investigator of the Heart and Stroke Foundation of Ontario. To whom correspondence should be addressed: London Health Sciences Centre, 339 Windermere Rd., London, ON N6A 5A5, Canada. Tel.: 519-663-3973; Fax: 519-434-3278; E-mail: gpickering{at}robarts.ca.

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