Abstract
Stimulation of a number of cell surface receptors, including integrins and G protein-coupled receptors, results in the activation of a non-receptor tyrosine kinase known as focal adhesion kinase (FAK). In turn, this kinase is believed to play a critical role in signaling to intracellular kinase cascades controlling gene expression such as extracellular signal-regulated kinases (ERKs), by a yet poorly defined mechanism. Furthermore, whether this tyrosine kinase also mediates the activation of other mitogen-activated protein kinase family members, such as c-Jun NH(2)-terminal kinases (JNKs), is still unclear. We show here that the activation of FAK by anchoring to the cell membrane is itself sufficient to stimulate potently both ERK and JNK. These effects were found to be phosphatidylinositol 3-kinase-independent, as FAK effectively stimulated Akt, and wortmannin suppressed Akt but not ERK or JNK activation. As previously reported by others, activation of ERK correlated with the ability of FAK to induce tyrosine phosphorylation of Shc. Surprisingly, however, stimulation of JNK was not dependent on the kinase activity of FAK or on the ability to induce tyrosine phosphorylation of FAK substrates. Instead, we provide evidence that FAK may stimulate JNK through a novel pathway involving the recruitment of paxillin to the plasma membrane and the subsequent activation of a biochemical route dependent on small GTP-binding proteins of the Rho family.
Highlights
From the ‡Oral and Pharyngeal Cancer Branch and §Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4330
Engagement of integrins and stimulation of G protein-coupled receptors (GPCRs) lead to the activation of focal adhesion kinase (FAK) and of many intracellular signaling path
As an experimental approach to investigate whether FAK can alone enhance the activity of mitogen-activated protein kinases (MAPKs), we overexpressed in 293T cells a wild type and a membrane-targeted form FAK
Summary
From the ‡Oral and Pharyngeal Cancer Branch and §Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4330. Stimulation of a number of cell surface receptors, including integrins and G protein-coupled receptors, results in the activation of a non-receptor tyrosine kinase known as focal adhesion kinase (FAK) This kinase is believed to play a critical role in signaling to intracellular kinase cascades controlling gene expression such as extracellular signal-regulated kinases (ERKs), by a yet poorly defined mechanism. Whether this tyrosine kinase mediates the activation of other mitogen-activated protein kinase family members, such as c-Jun NH2-terminal kinases (JNKs), is still unclear. In the case of JNKs, they have being shown to phosphorylate the transactivating domain of c-Jun and ATF2 [6], thereby increasing their transcriptional activity
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