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

Academic Article

Abstract

  • 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 kinaseinhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover. © 2012 Lim et al.
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    Digital Object Identifier (doi)

    Author List

  • Lim ST; Miller NLG; Chen XL; Tancioni I; Walsh CT; Lawson C; Uryu S; Weis SM; Cheresh DA; Schlaepfer DD
  • Start Page

  • 907
  • End Page

  • 919
  • Volume

  • 197
  • Issue

  • 7