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Gas6 anti-apoptotic signaling requires NF-kappa B activation

F Demarchi1, R Verardo, B Varnum

  • 1Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie AREA Science Park, Padriciano 99, Trieste 34012, Italy.

The Journal of Biological Chemistry
|June 27, 2001
PubMed

Insights

Growth arrest-specific 6 (Gas6) protein promotes cell survival by activating nuclear factor kappa B (NF-kappa B) signaling. This pathway involves phosphatidylinositol 3-OH kinase (PI3K), Akt, and glycogen synthase kinase 3, highlighting new links in anti-apoptotic signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Growth arrest-specific 6 (Gas6) is a secreted factor that binds to the Axl receptor tyrosine kinase.
  • Gas6 signaling activates phosphatidylinositol 3-OH kinase (PI3K) and Akt, promoting cell survival.
  • Previous studies indicated Gas6's anti-apoptotic role requires PI3K and Akt, involving Bad phosphorylation.

Purpose of the Study:

  • To investigate the role of nuclear factor kappa B (NF-kappa B) in Gas6-mediated anti-apoptotic signaling.
  • To elucidate the relationship between Gas6, PI3K/Akt pathway, and NF-kappa B activation.
  • To explore the involvement of glycogen synthase kinase 3 (GSK3) in Gas6 survival pathways.

Main Methods:

  • Assessed NF-kappa B binding activity and transcription using reporter assays.
  • Utilized dominant-negative inhibitors and specific inhibitors (wortmannin) to block signaling pathways.
  • Examined protein-protein interactions (GSK3 and NFKB1/p105) and protein levels via Western blotting and co-immunoprecipitation.

Main Results:

  • Gas6 rapidly increased nuclear NF-kappa B binding activity, leading to increased Bcl-x(L) protein levels and transcriptional activation.
  • Gas6's survival function was impaired in cells with inhibited NF-kappa B or its components (p65/RelA, I kappa B).
  • NF-kappa B activation was downstream of PI3K/Akt, and GSK3 was shown to associate with and phosphorylate NFKB1/p105, decreasing its protein level.

Conclusions:

  • NF-kappa B activation is crucial for Gas6-mediated cell survival.
  • Gas6 signaling involves a pathway linking PI3K/Akt to NF-kappa B activation.
  • GSK3 and NF-kappa B are implicated in Gas6's anti-apoptotic effects, suggesting novel survival pathway interactions.

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