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ADAM15 protein amplifies focal adhesion kinase phosphorylation under genotoxic stress conditions

Dorothee Fried1, Beate B Böhm, Kristin Krause

  • 1Division of Rheumatology, Goethe University Hospital Frankfurt am Main, 60590 Frankfurt am Main, Germany.

The Journal of Biological Chemistry
|May 1, 2012
PubMed

Insights

ADAM15 (a disintegrin and metalloproteinase) prevents genotoxic stress-induced apoptosis by suppressing caspase-3 activation. Its cytoplasmic tail is crucial for recruiting survival kinases like FAK and Src, enhancing cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • ADAM15 (a disintegrin and metalloproteinase) plays a role in cellular processes.
  • Genotoxic stress can induce apoptosis (programmed cell death).
  • The function of ADAM15's intracellular domain in stress response is not fully understood.

Purpose of the Study:

  • To investigate the role of ADAM15's cytoplasmic tail in counteracting genotoxic stress-induced apoptosis.
  • To elucidate the molecular mechanisms by which ADAM15 signaling pathways regulate cell survival.

Main Methods:

  • Utilized cell lines expressing full-length ADAM15 and ADAM15 mutants lacking the cytoplasmic tail.
  • Employed genotoxic stress induction using camptothecin.
  • Performed mammalian two-hybrid, pulldown, and far Western assays to study protein interactions.
  • Investigated phosphorylation of FAK (Focal Adhesion Kinase) and Src kinases.
  • Used chimeric constructs to assess signal transduction through the ADAM15 tail.
  • Tested the effects of FAK/Src signaling inhibitors.

Main Results:

  • Full-length ADAM15 expression suppressed camptothecin-induced apoptosis, while a mutant lacking the cytoplasmic tail did not.
  • ADAM15's cytoplasmic domain directly binds to FAK.
  • Genotoxic stress led to enhanced phosphorylation of FAK at specific sites (Tyr-397, Tyr-576, Tyr-861) and Src at Tyr-416 in cells expressing full-length ADAM15.
  • ADAM15 enhances FAK/Src activation, with FAK acting as an adaptor protein.
  • ADAM15 expression significantly reduced apoptosis induced by FAK/Src inhibitors.

Conclusions:

  • The cytoplasmic tail of ADAM15 is essential for its anti-apoptotic function against genotoxic stress.
  • ADAM15 acts as a scaffold, recruiting and activating FAK and Src kinases to promote chondrocytic cell survival.
  • This pathway may be relevant to apoptosis resistance in cancer.

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