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

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 p130^CAS, the phosphorylation of p130^CAS, 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.