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

J Biol Chem. 2008 Jun 27;283(26):18269-82. doi: 10.1074/jbc.M802156200. Epub 2008 Apr 17.


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 Asp(1016)/Asp(1019) to release a approximately 47-kDa product, which is subsequently proteolyzed by caspases at Asp(1125) 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-x(L)-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-x(L) 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-x(L) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis
  • Caspases / chemistry*
  • Caspases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cytochromes c / metabolism*
  • Humans
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sequence Homology, Amino Acid
  • bcl-Associated Death Protein / metabolism
  • bcl-X Protein / metabolism


  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Cytochromes c
  • Caspases