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 ac tivated by integrins, but not significantly by growth factor receptors. Her ein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors c ause more modest or no activation of this enzyme. Integrin-mediated stimula tion of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130(CAS), the phosphorylation of p130(CAS), and subsequentl y, the recruitment of Crk. Ras and PI-3K were not required. FAK-JNK signali ng was necessary for proper progression through the G1 phase of the cell cy cle. 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 fo r JNK signaling that is consistent with the role of Jun in both proliferati on and transformation.