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* Department of Pharmacology, Integrin-mediated cell adhesion causes activation of MAP kinases and increased tyrosine phosphorylation of focal adhesion kinase (FAK). Autophosphorylation of FAK leads to the binding of SH2-domain
proteins including Src-family kinases and the Grb2-Sos complex. Since Grb2-Sos is a key regulator of the Ras
signal transduction pathway, one plausible hypothesis
has been that integrin-mediated tyrosine phosphorylation of FAK leads to activation of the Ras cascade and
ultimately to mitogen activated protein (MAP) kinase activation. Thus, in this scenario FAK would serve as
an upstream regulator of MAP kinase activity. However, in this report we present several lines of evidence
showing that integrin-mediated MAP kinase activity in
fibroblasts is independent of FAK. First, a Department of Cell Biology, § Department of Pediatrics, Department of Anesthesiology,
School of Medicine, and ** Department of Periodontics, School of Dentistry, University of North Carolina, Chapel Hill,
North Carolina 27599
1 integrin subunit deletion mutant affecting the putative FAK
binding site supports activation of MAP kinase in adhering fibroblasts but not tyrosine phosphorylation of
FAK. Second, fibroblast adhesion to bacterially expressed fragments of fibronectin demonstrates that robust activation of MAP kinase can precede tyrosine
phosphorylation of FAK. Finally, we have used FRNK,
the noncatalytic COOH-terminal domain of FAK, as a
dominant negative inhibitor of FAK autophosphorylation and of tyrosine phosphorylation of focal contacts.
Using retroviral infection, we demonstrate that levels
of FRNK expression sufficient to completely block
FAK tyrosine phosphorylation were without effect on
integrin-mediated activation of MAP kinase. These results strongly suggest that integrin-mediated activation
of MAP kinase is independent of FAK and indicate the
probable existence of at least two distinct integrin signaling pathways in fibroblasts.
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