Integrin-mediated Activation of MAP Kinase Is Independent of FAK: Evidence for Dual Integrin Signaling Pathways in Fibroblasts
Open Access
- 24 March 1997
- journal article
- research article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 136 (6), 1385-1395
- https://doi.org/10.1083/jcb.136.6.1385
Abstract
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 beta1 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.Keywords
This publication has 91 references indexed in Scilit:
- Involvement of the Small GTPase Rho in Integrin-mediated Activation of Mitogen-activated Protein KinasePublished by Elsevier BV ,1996
- Ras Activation Is Necessary for Integrin-mediated Activation of Extracellular Signal-regulated Kinase 2 and Cytosolic Phospholipase A2 but Not for Cytoskeletal OrganizationPublished by Elsevier BV ,1996
- Expression of the Integrin α5 Subunit in HT29 Colon Carcinoma Cells Suppresses Apoptosis Triggered by Serum DeprivationExperimental Cell Research, 1996
- Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient miceNature, 1995
- Stat5 as a Target for Regulation by Extracellular MatrixPublished by Elsevier BV ,1995
- Integrin-mediated Tyrosine Phosphorylation and Cytokine Message Induction in Monocytic Cells: A POSSIBLE SIGNALING ROLE FOR THE Syk TYROSINE KINASEPublished by Elsevier BV ,1995
- Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions.The Journal of cell biology, 1993
- Functional role of the cytoplasmic domain of the integrin alpha 5 subunitThe Journal of cell biology, 1993
- Identification of amino acid sequences in the integrin beta 1 cytoplasmic domain implicated in cytoskeletal associationThe Journal of cell biology, 1992
- Integrins: Versatility, modulation, and signaling in cell adhesionCell, 1992