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


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

SUBMITTER: Lim ST 

PROVIDER: S-EPMC3384409 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Lim Ssang-Taek ST   Miller Nichol L G NL   Chen Xiao Lei XL   Tancioni Isabelle I   Walsh Colin T CT   Lawson Christine C   Uryu Sean S   Weis Sara M SM   Cheresh David A DA   Schlaepfer David D DD  

The Journal of cell biology 20120601 7


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-assoc  ...[more]

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