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

• Published in: The Journal of cell biology 2012-06, Vol.197 (7), p.907-919
• Main Authors: Lim, Ssang-Taek, Miller, Nichol L G, Chen, Xiao Lei, Tancioni, Isabelle, Walsh, Colin T, Lawson, Christine, Uryu, Sean, Weis, Sara M, Cheresh, David A, Schlaepfer, David D
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Animals; Cell adhesion & migration; Cell Nucleus - metabolism; Cells, Cultured; Embryo, Mammalian - metabolism; Endothelium; Enzyme Activation; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; GATA4 Transcription Factor - metabolism; Gene expression; Gene Expression Regulation, Developmental; Humans; Kinases; Mice; Mice, Transgenic; Pharmacology; Proteins; TNF inhibitors; Tumor Necrosis Factor-alpha - metabolism; Ubiquitination; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201109067

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.