| First Author | Lim ST | Year | 2012 |
| Journal | J Cell Biol | Volume | 197 |
| Issue | 7 | Pages | 907-19 |
| PubMed ID | 22734001 | Mgi Jnum | J:185347 |
| Mgi Id | MGI:5428342 | Doi | 10.1083/jcb.201109067 |
| Citation | Lim ST, et al. (2012) Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. J Cell Biol 197(7):907-19 |
| abstractText | Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-alpha (TNF-alpha) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin-matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-alpha-induced VCAM-1 expression within heart vessel-associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-alpha-induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-alpha-induced VCAM-1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase-dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover. |
