J. Cell Biol., Volume 144, Number 2, January 25, 1999 315-324

Dissociation of FAK/p130^CAS/c-Src Complex during Mitosis: Role of Mitosis-specific Serine Phosphorylation of FAK

Yoshihiko Yamakita,^* Go Totsukawa,^* Shigeko Yamashiro,^* David Fry, Xiaoe Zhang,^§ Steven K. Hanks,^§ and Fumio Matsumura^*

^* Department of Molecular Biology and Biochemistry, Rutgers University, Nelson Labs, Piscataway, New Jersey 08855;  Department of Cancer Research, Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105; ^§ Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and  Cancer Institute of New Jersey, Busch Campus, Piscataway, New Jersey 08855

At mitosis, focal adhesions disassemble and the signal transduction from focal adhesions is inactivated. We have found that components of focal adhesions including focal adhesion kinase (FAK), paxillin, and p130^CAS (CAS) are serine/threonine phosphorylated during mitosis when all three proteins are tyrosine dephosphorylated. Mitosis-specific phosphorylation continues past cytokinesis and is reversed during post-mitotic cell spreading.

We have found two significant alterations in FAK-mediated signal transduction during mitosis. First, the association of FAK with CAS or c-Src is greatly inhibited, with levels decreasing to 16 and 13% of the interphase levels, respectively. Second, mitotic FAK shows decreased binding to a peptide mimicking the cytoplasmic domain of beta-integrin when compared with FAK of interphase cells. Mitosis-specific phosphorylation is responsible for the disruption of FAK/CAS binding because dephosphorylation of mitotic FAK in vitro by protein serine/threonine phosphatase 1 restores the ability of FAK to associate with CAS, though not with c-Src. These results suggest that mitosis-specific modification of FAK uncouples signal transduction pathways involving integrin, CAS, and c-Src, and may maintain FAK in an inactive state until post-mitotic spreading.

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