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(Received for publication, May 22, 1997, and in revised form, July 30, 1997)
From the Integrin-ligand binding induces the tyrosine
phosphorylation of various proteins including focal adhesion kinase
(pp125FAK) and Crk-associated substrate (Cas). FAK is
activated and autophosphorylated by the ligation of integrins, although
the substrate of FAK has not been revealed. We show here that
p130Cas and Cas-L are FAK substrates. FAK directly
phosphorylates Cas proteins primarily at the YDYVHL sequence that is
conserved among all Cas proteins. Furthermore, the phosphorylated
YDYVHL sequence is a binding site for Src family protein-tyrosine
kinases, and the recruited Src family kinase phosphorylates the other
tyrosine residues within Cas. The Cas-L YDYVHL sequence is
phosphorylated upon integrin-ligand binding, and this integrin-mediated
tyrosine phosphorylation is inhibited by the cotransfection of the FAK COOH-terminal domain that does not contain a kinase domain. These findings strongly suggest that FAK initiates integrin-mediated tyrosine
phosphorylation of Cas proteins; then, Src family tyrosine kinases,
which are recruited to phosphorylated Cas and FAK, further phosphorylate Cas proteins.
Volume 272, Number 46,
Issue of November 14, 1997
pp. 29083-29090
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Tyrosine Phosphorylation of Crk-associated Substrates by
Focal Adhesion Kinase
A PUTATIVE MECHANISM FOR THE INTEGRIN-MEDIATED TYROSINE
PHOSPHORYLATION OF Crk-ASSOCIATED SUBSTRATES
,
,
,
,
,
and**
Department of Cancer Immunology and AIDS,
Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts 02115, the ¶ Department of Biochemistry, Tufts
University School of Medicine, Boston, Massachusetts 02111, the
Third Department of Internal Medicine, Faculty of Medicine,
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan, and the
** Department of Clinical Immunology and AIDS Research Center, Institute
of Medical Science, University of Tokyo, 4-6-1, Shiroganedai,
Minato-ku, Tokyo 108, Japan
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