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

Anne M. Strohecker, Fruma Yehiely, Feng Chen, Vincent L. Cryns

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Human epidermal growth factor receptor-2 (HER-2/ErbB2/neu), a receptor tyrosine kinase that is amplified/overexpressed in poor prognosis breast carcinomas, confers resistance to apoptosis by activating cell survival pathways. Here we demonstrate that the cytoplasmic tail of HER-2 is cleaved by caspases at Asp1016/Asp1019 to release a ∼47-kDa product, which is subsequently proteolyzed by caspases at Asp1125 into an unstable 22-kDa fragment that is degraded by the proteasome and a predicted 25-kDa product. Both the 47- and 25-kDa products translocate to mitochondria, release cytochrome c by a Bcl-xL-suppressible mechanism, and induce caspase-dependent apoptosis. The 47- and 25-kDa HER-2 cleavage products share a functional BH3-like domain, which is required for cytochrome c release in cells and isolated mitochondria and for apoptosis induction. Caspase-cleaved HER-2 binds Bcl-xL and acts synergistically with truncated Bid to induce apoptosis, mimicking the actions of the BH3-only protein Bad. Moreover, the HER-2 cleavage products cooperate with Noxa to induce apoptosis in cells expressing both Bcl-xL and Mcl-1, confirming their Bad-like function. Collectively, our results indicate that caspases activate a previously unrecognized proapoptotic function of HER-2 by releasing a Bad-like cell death effector.

Original languageEnglish (US)
Pages (from-to)18269-18282
Number of pages14
JournalJournal of Biological Chemistry
Volume283
Issue number26
DOIs
StatePublished - Jun 27 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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