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© The Rockefeller University Press, 0021-9525/1999//1461 $5.00
The Journal of Cell Biology, Volume 145, Number 7, , 1999 1461-1470

Regular Articles

Integrin-mediated Activation of Focal Adhesion Kinase Is Required for Signaling to Jun NH2-terminal Kinase and Progression through the G1 Phase of the Cell Cycle



Maja Oktay*, Kishore K. Wary*, Michael Dans*, Raymond B. Birge{ddagger}, and Filippo G. Giancotti*

* Laboratory of Cell Adhesion and Signaling, Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York 10021; and {ddagger} Laboratory of Molecular Oncology, The Rockefeller University, New York 10021

The extracellular matrix exerts a stringent control on the proliferation of normal cells, suggesting the existence of a mitogenic signaling pathway activated by integrins, but not significantly by growth factor receptors. Herein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors cause more modest or no activation of this enzyme. Integrin-mediated stimulation of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130CAS, the phosphorylation of p130CAS, and subsequently, the recruitment of Crk. Ras and PI-3K were not required. FAK–JNK signaling was necessary for proper progression through the G1 phase of the cell cycle. These findings establish a role for FAK in both the activation of JNK and the control of the cell cycle, and identify a physiological stimulus for JNK signaling that is consistent with the role of Jun in both proliferation and transformation.

Key Words: integrins • focal adhesion kinase • Jun NH2-terminal kinase • Jun • cell cycle

Abbreviations used in this paper: ATF2, activating transcrition factor 2; BrdU, 5-bromodeoxyuridine; CS, calf serum; CMV, cytomegalovirus; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GST, glutathione S-transferase; HUVECs, human umbilical vein endothelial cells; JNK, Jun NH2-terminal kinase; PDGF, platelet-derived growth factor; SD, substrate region deleted; SFM, serum-free medium; SRE, serum response element; TPA, 12-O-tetradecanoylphorbol-13-acetate; TRE, TPA-responsive element.

Maja Oktay's present address is Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.


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