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Molecular and Cellular Biology, June 2006, p. 4201-4213, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01612-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms

Patrick Bryant, Qingxia Zheng, and Kevin Pumiglia*

Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208

Received 19 August 2005/ Returned for modification 7 October 2005/ Accepted 13 March 2006

Endothelial cell proliferation is a critical step in angiogenesis and requires a coordinated response to soluble growth factors and the extracellular matrix. As focal adhesion kinase (FAK) integrates signals from both adhesion events and growth factor stimulation, we investigated its role in endothelial cell proliferation. Expression of a dominant-negative FAK protein, FAK-related nonkinase (FRNK), impaired phosphorylation of FAK and blocked DNA synthesis in response to multiple angiogenic stimuli. These results coincided with elevated cyclin-dependent kinase inhibitors (CDKIs) p21/Cip and p27/Kip, as a consequence of impaired degradation. FRNK inhibited the expression of Skp2, an F-box protein that targets CDKIs, by inhibiting mitogen-induced mRNA. The FAK-regulated degradation of p27/Kip was Skp2 dependent, while levels of p21/Cip were regulated independent of Skp2. Skp2 is required for endothelial cell proliferation as a consequence of degrading p27. Finally, knockdown of both p21 and p27 in FRNK-expressing cells completely restored mitogen-induced endothelial cell proliferation. These data demonstrate a critical role for FAK in the regulation of CDKIs through two independent mechanisms: Skp2 dependent and Skp2 independent. They also provide important insights into the requirement of focal adhesion kinase for normal vascular development and reveal novel regulatory control points for angiogenesis.

* Corresponding author. Mailing address: Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. Phone: (518) 262-6587. Fax: (518) 262-5696. E-mail: pumiglk{at}amc.edu.

Molecular and Cellular Biology, June 2006, p. 4201-4213, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01612-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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