Caspase cleavage of HER-2 releases a Bad-like cell death effector.
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.
Strohecker
Anne M
AM
Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Yehiely
Fruma
F
Chen
Feng
F
Cryns
Vincent L
VL
D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D020169:Caspases