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Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway

Akihisa Nakagawa1, Kelly D Sullivan1, Ding Xue1

  • 1Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, Colorado, USA.

Nature Structural & Molecular Biology
|November 11, 2014
PubMed

Insights

A newly identified protein fragment, tCNT-1, inhibits the AKT pathway during apoptosis. This discovery reveals a novel mechanism for suppressing cell survival signals and promoting programmed cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Apoptosis requires inactivating cell-survival factors.
  • The PI3K-AKT pathway promotes cell survival and growth; its dysregulation is linked to cancer.
  • Mechanisms suppressing AKT signaling during apoptosis are not well understood.

Purpose of the Study:

  • To identify novel mechanisms that regulate the PI3K-AKT pathway during apoptosis.
  • To elucidate how AKT prosurvival activity is suppressed to promote programmed cell death.

Main Methods:

  • Identified CNT-1 as a substrate for CED-3 caspase in C. elegans.
  • Characterized the cleavage of CNT-1 during apoptosis.
  • Investigated the subcellular localization and function of the tCNT-1 fragment.

Main Results:

  • Cleavage of CNT-1 generates a phosphoinositide-binding fragment (tCNT-1).
  • tCNT-1 translocates to the plasma membrane and inhibits AKT activation by blocking its binding to phosphatidylinositol (3,4,5)-trisphosphate.
  • This inhibition disables AKT's prosurvival activity, promoting apoptosis.

Conclusions:

  • A novel mechanism for negative regulation of AKT signaling in apoptosis has been identified.
  • The tCNT-1 fragment plays a critical role in suppressing AKT-mediated cell survival.
  • This pathway may also restrict cell growth and proliferation in normal physiological conditions.

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