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Molecular and Cellular Biology, November 2003, p. 8030-8041, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8030-8041.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Focal Adhesion Kinase by Its Amino-Terminal Domain through an Autoinhibitory Interaction

Lee Ann Cooper, Tang-Long Shen, and Jun-Lin Guan*

Department of Molecular Medicine, Cornell University, Ithaca, New York 14853

Received 19 February 2003/ Returned for modification 28 April 2003/ Accepted 16 August 2003

We have investigated a role for the amino-terminal FERM-like domain of the focal adhesion kinase (FAK) as a negative regulator of its own activity and phosphorylation state. Deletion of the first 375 amino acids from the amino terminus of FAK increases its catalytic activity in vitro, its phosphorylation when expressed in mammalian cells, and the phosphorylation of a FAK substrate, paxillin. Deletion mutants are phosphorylated in suspension, suggesting that they are no longer regulated by adhesion. The amino terminus of FAK can interact with the kinase domain of FAK in vitro and in vivo, suggesting that it might act as an autoinhibitor of FAK activity. The amino terminus of FAK can act in trans to inhibit FAK phosphorylation when expressed in mammalian cells or to directly inhibit FAK activity in vitro. Expression of the amino terminus of FAK inhibits cell cycle progression in CHO cells, consistent with its inhibition of FAK phosphorylation and function in trans. A glutathione S-transferase fusion protein containing the cytoplasmic tail of the ß1 integrin stimulates FAK activity in vitro, suggesting that FAK could be regulated by molecular interactions with the amino terminus. Based on these and previous data, we propose a working model for activation of FAK in cell adhesion.

* Corresponding author. Mailing address: Department of Molecular Medicine, Cornell University, Ithaca, NY 14853. Phone: (607) 253-3586. Fax: (607) 253-3708. E-mail: jg19{at}cornell.edu.

Molecular and Cellular Biology, November 2003, p. 8030-8041, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8030-8041.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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