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A more recent version of this article appeared on September 1, 2002
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Submitted on November 30, 2001
Revised on May 22, 2002
Accepted on June 5, 2002
1 Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
* Corresponding author. E-mail address: jg19{at}cornell.edu.
Focal adhesion kinase (FAK) is a major mediator of integrin signaling pathways. The mechanisms of regulation of FAK activity and its associated cellular functions are not very well understood. Here we present data suggesting that a novel protein FIP200 functions as an inhibitor for FAK. We showed that association of endogenous FIP200 with FAK, which is decreased upon integrin-mediated cell adhesion concomitant with FAK activation. In vitro and in vivo binding studies indicated that FIP200 interacts with FAK through multiple domains directly. FIP200 bound to the kinase domain of FAK, inhibited its kinase activity in vitro, and its autophosphorylation in vivo. Overexpression of FIP200 or its segments inhibited cell spreading, cell migration and cell cycle progression, which correlated with their inhibition of FAK activity in vivo. The inhibition of these cellular functions by FIP200 could be rescued by co-expression of FAK. Lastly, we show that disruption of the functional interaction between endogenous FIP200 with FAK led to increased FAK phosphorylation and partial restoration of cell cycle progression in cells plated on poly-L-lysine, providing further support for FIP200 as a negative regulator of FAK. Together, these results identify FIP200 as a novel protein inhibitor for FAK.
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