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© The Rockefeller University Press, 0021-9525/1998//1997 $5.00
The Journal of Cell Biology, Volume 143, Number 7, , 1998 1997-2008

Regular Articles

Regulation of the Cell Cycle by Focal Adhesion Kinase



Ji-He Zhao, Heinz Reiske, and Jun-Lin Guan

Cancer Biology Laboratories, Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

In this report, we have analyzed the potential role and mechanisms of integrin signaling through FAK in cell cycle regulation by using tetracycline-regulated expression of exogenous FAK and mutants. We have found that overexpression of wild-type FAK accelerated G1 to S phase transition. Conversely, overexpression of a dominant-negative FAK mutant {Delta}C14 inhibited cell cycle progression at G1 phase and this inhibition required the Y397 in {Delta}C14. Biochemical analyses indicated that FAK mutant {Delta}C14 was mislocalized and functioned as a dominant-negative mutant by competing with endogenous FAK in focal contacts for binding signaling molecules such as Src and Fyn, resulting in a decreases of Erk activation in cell adhesion. Consistent with this, we also observed inhibition of BrdU incorporation and Erk activation by FAK Y397F mutant and FRNK, but not FRNK{Delta}C14, in transient transfection assays using primary human foreskin fibroblasts. Finally, we also found that {Delta}C14 blocked cyclin D1 upregulation and induced p21 expression, while wild-type FAK increased cyclin D1 expression and decreased p21 expression. Taken together, these results have identified FAK and its associated signaling pathways as a mediator of the cell cycle regulation by integrins.

Key Words: FAK • cell cycle • inducible expression • integrin signaling • focal contacts

Abbreviations used in this paper: BrdU, 5-bromodeoxyuridine; CDK, cyclin-dependent kinase; CS, calf serum; E4Y1, poly(Glu,Tyr); Erk, extracellular signal–regulated kinase; FAK, focal adhesion kinase; FN, fibronectin; MBP, myelin basic protein; PI 3-kinase, phosphatidylinositol 3-kinase; SH2, Src homology 2; WT, wild type.

This research was supported by National Institutes of Health grant GM52890 to J.-L. Guan. J.-L. Guan is an Established Investigator of American Heart Association.


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