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Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner

Kunyan He1, Sung-Wuk Jang, Jayashree Joshi

  • 1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Molecular Biology of the Cell
|April 5, 2011
PubMed

Insights

Akt phosphorylates PIKE-A, inhibiting the tumor suppressor UNC5B and p53-dependent apoptosis. This pathway, involving PIKE-A GTPase and Akt kinase activity, impacts cancer cell survival and tumor suppression mechanisms.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • UNC5B functions as a tumor suppressor, inducing apoptosis independently of netrins.
  • UNC5B is a transcriptional target of p53, activated by UV radiation.

Purpose of the Study:

  • To investigate the role of Akt and PIKE-A in regulating UNC5B-mediated apoptosis.
  • To elucidate the molecular mechanism by which Akt-phosphorylated PIKE-A influences UNC5B expression and p53 activity.

Main Methods:

  • Investigated protein-protein interactions between Akt, PIKE-A, and UNC5B.
  • Utilized PIKE knockout (PIKE-/-) Mouse Embryonic Fibroblast (MEF) cells and wild-type controls.
  • Examined the effects of PIKE-A overexpression and knockdown on p53, UNC5B, and UV-triggered apoptosis.
  • Assessed the impact of Akt depletion on PIKE-A's regulatory functions.

Main Results:

  • Akt phosphorylates PIKE-A, enhancing its kinase activity and interaction with UNC5B.
  • PIKE-A overexpression down-regulates p53 and diminishes UNC5B expression.
  • PIKE-A knockdown stabilizes p53, up-regulates UNC5B, and potentiates UV-induced apoptosis.
  • Akt activity is crucial for PIKE-A's inhibitory effects on p53 and UNC5B.

Conclusions:

  • Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis by inactivating p53.
  • This molecular axis represents a novel regulatory pathway influencing tumor suppression and apoptosis.

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