Figure 8.

Model of FAK function downstream of TNF-α in the regulation of VCAM-1 expression. TNF-α binding to cell surface receptors triggers intracellular signaling cascade activation of MAPKs and NF-κB. This leads to alterations in gene transcription of targets such as VCAM-1 that is regulated in part by combined effects of AP-1, GATA, and NF-κB transcription factors. Inhibition of FAK prevents TNF-α–induced MAPK activation and the inhibition of GATA4 Ser105 phosphorylation. Inhibited FAK (FAK-KD) accumulates in the nucleus, binds directly to GATA4, and promotes increased GATA4 ubiquitination and proteasomal degradation via interactions with the CHIP E3 ubiquitin ligase. Impairment in both FAK-mediated MAPK activation and GATA4 stability prevent cytokine-stimulated VCAM-1 transcription and reveal novel anti-inflammatory effects of FAK inhibition.