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

The Journal of Biological Chemistry
Anne M StroheckerVincent L Cryns

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 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...Continue Reading

References

Jul 1, 1992·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·B A GustersonR Reed
Mar 1, 1996·The Journal of Biological Chemistry·A M ChinnaiyanV M Dixit
Nov 15, 1996·Genes & Development·K WangS J Korsmeyer
Jan 1, 1997·Methods : a Companion to Methods in Enzymology·K McClainB B Aggarwal
Jan 7, 1998·Science·E H ChengJ M Hardwick
Jan 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·R J ClemJ M Hardwick
Jun 17, 1998·Genes & Development·V Cryns, J Yuan
Jul 4, 1998·Molecular Cell·S M SrinivasulaE S Alnemri
Sep 19, 1998·Molecular and Cellular Biology·K WangS J Korsmeyer
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·L MengC M Crews
Mar 14, 2000·The Journal of Biological Chemistry·B P ZhouM C Hung
Oct 12, 2000·Nature Cell Biology·M LutterX Wang
Jun 13, 2001·The Journal of Biological Chemistry·O Tikhomirov, G Carpenter
Jun 26, 2001·Cell Death and Differentiation·Y ByunV L Cryns
Jul 21, 2001·Molecular Cell·K Nakano, K H Vousden
Nov 21, 2001·Nature Cell Biology·B P ZhouM C Hung
Dec 14, 2001·The Journal of Biological Chemistry·Muniswamy MadeshGyörgy Hajnóczky
Mar 5, 2002·The Journal of Biological Chemistry·Feng ChenVincent L Cryns
Jul 2, 2003·The Journal of Biological Chemistry·Hong LiuSarah Spiegel
Apr 17, 2004·The Journal of Biological Chemistry·Feng ChenVincent L Cryns
Oct 16, 2004·The Journal of Biological Chemistry·Carlo RodolfoMauro Piacentini
Mar 23, 2005·Oncogene·Oleg TikhomirovGraham Carpenter
May 3, 2005·Nature Reviews. Cancer·Nancy E Hynes, Heidi A Lane

❮ Previous
Next ❯

Citations

Mar 20, 2010·Nature Reviews. Cancer·Carlos López-Otín, Tony Hunter
Jul 31, 2009·Oncogene·E Lomonosova, G Chinnadurai
Feb 23, 2010·Oncogene·D Goldschneider, P Mehlen
Jan 9, 2010·BMC Genomics·Lawrence J K WeeShoba Ranganathan
Jul 25, 2012·BMC Medicine·Parul Gupta, Sanjay K Srivastava
Feb 28, 2013·Therapeutic Delivery·Neelesh Kumar MehraNarendra K Jain
Oct 28, 2008·Experimental Cell Research·Graham Carpenter, Hong-Jun Liao
Jan 8, 2015·The FEBS Journal·Marcel DoerflingerHamsa Puthalakath
Sep 10, 2009·Cell·Manabu Kurokawa, Sally Kornbluth
May 24, 2018·FEBS Letters·Matthew KreitmanYosef Yarden
Feb 12, 2014·Particle & Particle Systems Characterization : Measurement and Description of Particle Properties and Behavior in Powders and Other Disperse Systems·Bong Jin HongSonbinh T Nguyen
Feb 25, 2020·ELife·Leslie DuplaquetDavid Tulasne
Jun 1, 2009·Toxicological Research·Jung-Hwa OhSeokjoo Yoon
Nov 18, 2020·Biochemistry. Biokhimii︠a︡·A A DaksN A Barlev
May 6, 2021·Biomolecules·Hao Huang
Dec 10, 2013·Macromolecules·Sang-Min Lee, SonBinh T Nguyen

❮ Previous
Next ❯

Related Concepts

Related Feeds

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis