Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.

Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 0375356 Publication Model: Print Cited Medium: Internet ISSN: 1540-8140 (Electronic) Linking ISSN: 00219525 NLM ISO Abbreviation: J Cell Biol Subsets: MEDLINE

Original Publication: New York : Rockefeller University Press

Cell Nucleus/*metabolism ; Focal Adhesion Kinase 1/*metabolism ; Vascular Cell Adhesion Molecule-1/*metabolism; Active Transport, Cell Nucleus ; Animals ; Cells, Cultured ; Embryo, Mammalian/metabolism ; Enzyme Activation ; Focal Adhesion Kinase 1/genetics ; GATA4 Transcription Factor/metabolism ; Gene Expression Regulation, Developmental ; Humans ; Mice ; Mice, Transgenic ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitination

Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-α (TNF-α) 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-α-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-α-induced, mitogen-activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-α-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.

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200810MFE-193594-139144 Canada CAPMC CIHR; R01 CA102310 United States CA NCI NIH HHS; GM087400 United States GM NIGMS NIH HHS; R01 HL103956 United States HL NHLBI NIH HHS; F32 CA159558 United States CA NCI NIH HHS; R01 GM087400 United States GM NIGMS NIH HHS; R01 HL093156 United States HL NHLBI NIH HHS; 1F32CA159558 United States CA NCI NIH HHS; HL093156 United States HL NHLBI NIH HHS

0 (GATA4 Transcription Factor)
0 (Gata4 protein, mouse)
0 (Tumor Necrosis Factor-alpha)
0 (Vascular Cell Adhesion Molecule-1)
EC 2.7.10.2 (Focal Adhesion Kinase 1)
EC 2.7.10.2 (Ptk2 protein, mouse)

Date Created: 20120627 Date Completed: 20120831 Latest Revision: 20211021

20221213

PMC3384409

10.1083/jcb.201109067

22734001