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Tumor necrosis factor-induced nuclear factor kappaB activation is impaired in focal adhesion kinase-deficient

Megumi Funakoshi-Tago1, Yoshiko Sonoda, Saeko Tanaka

  • 1Department of Biochemistry, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

The Journal of Biological Chemistry
|May 16, 2003
PubMed

Insights

Focal adhesion kinase (FAK) is crucial for tumor necrosis factor (TNF)-induced nuclear factor kappa B (NF-κB) activation and interleukin-6 (IL-6) production in fibroblasts. Restoring FAK rescues this inflammatory signaling pathway.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Signaling

Background:

  • Focal adhesion kinase (FAK) is recognized for its roles in cell proliferation, migration, and survival.
  • The involvement of FAK in immune and inflammatory responses remains largely unexplored.

Purpose of the Study:

  • To investigate the role of FAK in tumor necrosis factor (TNF)-induced inflammatory signaling.
  • To elucidate the specific molecular mechanisms by which FAK influences NF-kappaB activation and cytokine production.

Main Methods:

  • Utilized FAK-deficient (FAK-/-) embryonic fibroblasts to assess TNF-induced responses.
  • Analyzed NF-kappaB DNA binding activity, IkappaB kinase (IKK) activation, and protein-protein interactions (FAK-RIP, RIP-TRAF2, RIP-IKK complex).
  • Restored FAK function in FAK-/- cells to confirm its role in the pathway.

Main Results:

  • TNF-induced nuclear factor kappa B (NF-κB) activation and interleukin-6 (IL-6) production were significantly impaired in FAK-/- fibroblasts.
  • FAK deficiency did not affect other signaling pathways like ERK, JNK, p38, or activator protein 1.
  • FAK is essential for the TNF-induced association of receptor-interacting protein (RIP) with TNF receptor-associated factor 2 (TRAF2) and subsequent recruitment of the IKK complex, which is critical for NF-κB activation.

Conclusions:

  • Focal adhesion kinase (FAK) plays a critical, previously unrecognized role in the tumor necrosis factor (TNF)-induced NF-kappaB signaling pathway.
  • FAK acts upstream of IKK complex recruitment, mediating the interaction between RIP and TRAF2, thereby regulating cytokine production.
  • This study identifies FAK as a novel regulator of inflammatory responses, specifically in the context of TNF-mediated NF-kappaB activation and IL-6 synthesis.

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