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© The Rockefeller University Press, 0021-9525/1997//1385 $5.00
The Journal of Cell Biology, Volume 136, Number 6, , 1997 1385-1395

Article

Integrin-mediated Activation of MAP Kinase Is Independent of FAK: Evidence for Dual Integrin Signaling Pathways in Fibroblasts



Tsung H. Lin*, Andrew E. Aplin*, Yu Shen{ddagger}, Qiming Chen*, Michael Schaller{ddagger}, Lewis Romer§,||, Ikramuddin Aukhil**, and R.L. Juliano*

* Department of Pharmacology, {ddagger} 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

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 β1 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.

Abbreviations used in this paper: FAK, pp125 focal adhesion kinase; Fn, fibronectin; FRNK, FAK-related nonkinase; MAP, mitogen activated protein; MEK, MAP kinase kinase; WT, wild type.

The EEEEYMPME epitope–tagged rat MEK-1 construct (EE-MEK) was kindly provided by Dennis J. Templeton (Case Western Reserve University, Cleveland, OH). A.R. Horwitz (University of Illinois, Urbana, IL) generously provided the chicken β1 constructs as well as the W1B10 monoclonal antibody.

Please address all correspondence to R.L. Juliano, Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599. Ph.: (919) 966-4383; Fax: (919) 966-5640.


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