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Caspase cleavage of HER-2 releases a Bad-like cell death effector

Anne M Strohecker1, Fruma Yehiely, Feng Chen

  • 1Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

The Journal of Biological Chemistry
|April 19, 2008
PubMed

Insights

Caspases cleave Human Epidermal Growth Factor Receptor-2 (HER-2) to release fragments that induce apoptosis. These HER-2 fragments act as a Bad-like effector, promoting programmed cell death in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Human Epidermal Growth Factor Receptor-2 (HER-2) is overexpressed in aggressive breast cancers, promoting survival.
  • HER-2 signaling pathways are implicated in resistance to apoptosis.

Purpose of the Study:

  • To investigate the role of caspase-mediated cleavage of HER-2 in apoptosis.
  • To identify the functional consequences of HER-2 cytoplasmic tail cleavage products.

Main Methods:

  • Western blotting and mass spectrometry to identify HER-2 cleavage sites and products.
  • Mitochondrial fractionation and cytochrome c release assays.
  • Cell-based apoptosis assays and co-immunoprecipitation.

Main Results:

  • Caspases cleave HER-2 at Asp(1016)/Asp(1019) and Asp(1125), generating 47-kDa and 25-kDa fragments.
  • These HER-2 fragments translocate to mitochondria, induce cytochrome c release, and trigger apoptosis.
  • The cleavage products possess a BH3-like domain, enabling interaction with Bcl-x(L) and mimicking the proapoptotic function of Bad.

Conclusions:

  • Caspase-mediated HER-2 cleavage uncovers a novel proapoptotic function.
  • HER-2 cleavage products act as Bad-like effectors, promoting cancer cell death.
  • This mechanism offers a potential therapeutic target in HER-2-overexpressing cancers.

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