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J. Biol. Chem., Vol. 279, Issue 36, 37304-37310, September 3, 2004

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Focal Adhesion Kinase (FAK)-dependent Regulation of S-phase Kinase-associated Protein-2 (Skp-2) Stability

A NOVEL MECHANISM REGULATING SMOOTH MUSCLE CELL PROLIFERATION^*

Mark Bond, Graciela B. Sala-Newby, and Andrew C. Newby

From the Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, United Kingdom

Smooth muscle cell (SMC) proliferation is suppressed in intact blood vessels but stimulated in atherosclerosis, restenosis after angioplasty, and vein graft disease. The cyclin-dependent kinase inhibitors, including p27^Kip1, play important roles in maintaining SMC quiescence. Levels of p27^Kip1 are dependent on attachment to and the composition of the extracellular matrix (ECM). Here we sought to elucidate mechanisms underlying the ECM-dependent regulation of p27^Kip1 and hence, SMC proliferation. Serum stimulation decreased p27^Kip1 levels in isolated SMC but not in rat aorta. The effect was post-translational and mediated by proteasomal degradation. We studied the S-phase-associated kinase protein-2 (Skp-2), an F-box protein involved in ubiquitination and proteasome-mediated degradation. Skp-2 protein is strongly induced by serum from undetectable levels in isolated SMCs but remains undetectable in aorta; Skp-2 mRNA is also lower in aorta. Overexpression of wild-type Skp-2 in SMCs decreased p27^Kip1 levels, whereas dominant negative F-box deleted mutant (F-Skp-2) Skp-2 increased p27^Kip1 levels. Furthermore, hyperphosphorylation of retinoblastoma protein and SMC proliferation were also reciprocally affected by wild-type and dominant negative Skp-2. Skp-2 expression was absolutely dependent on cell attachment to the ECM and was inhibited by laminin and type-1 fibrillar collagen but increased by fibronectin. Expression of Skp-2 protein, but not mRNA, was associated with focal adhesion kinase (FAK) activity and inhibited by overexpression of FAK-related non-kinase and a dominant negative FAK_Y397F mutant. Furthermore, the inhibition of Skp-2 expression by dominant negative FAK was reversed by the proteasome inhibitor MG-132. Taken together, these data demonstrate that the vascular ECM controls SMC proliferation via FAK-dependent regulation of Skp-2 protein stability.

Received for publication, April 19, 2004 , and in revised form, June 18, 2004.

^* This work was supported by the British Heart Foundation. 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 two supplemental figures.

To whom correspondence should be addressed. Tel.: 44-0-117-928-3587; Fax: 44-0-117-928-3581; E-mail: mark.bond{at}bris.ac.uk.

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