Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression.
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.
Department of Reproductive Medicine, University of California-San Diego, Moores Cancer Center, La Jolla, CA 92093, USA. stlim@usouthal.edu
Ssang-Taek
ST
Lim
Nichol L G
NL
Miller
Xiao Lei
XL
Chen
Isabelle
I
Tancioni
Colin T
CT
Walsh
Christine
C
Lawson
Sean
S
Uryu
Sara M
SM
Weis
David A
DA
Cheresh
David D
DD
Schlaepfer
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse