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Cell Death Dis. 2014 Mar 20;5:e1131. doi: 10.1038/cddis.2014.79.

P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP.

Author information

1
Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
2
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
3
Department of Anatomy, Sungkyunkwan University School of Medicine, Suwon, Korea.
4
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea.
5
Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul, Korea.

Abstract

The short isoform of ErbB3-binding protein 1 (Ebp1), p42, is considered to be a potent tumor suppressor in a number of human cancers, although the mechanism by which it exerts this tumor-suppressive activity is unclear. Here, we report that p42 interacts with the cSH2 domain of the p85 subunit of phosphathidyl inositol 3-kinase (PI3K), leading to inhibition of its lipid kinase activity. Importantly, we found that p42 induces protein degradation of the p85 subunit and further identified HSP70/CHIP complex as a novel E3 ligase for p85 that is responsible for p85 ubiquitination and degradation. In this process, p42 couples p85 to the HSP70/CHIP-mediated ubiquitin-proteasomal system (UPS), thereby promoting a reduction of p85 levels both in vitro and in vivo. Thus, the tumor-suppressing effects of p42 in cancer cells are driven by negative regulation of the p85 subunit of PI3K.

PMID:
24651434
PMCID:
PMC3973206
DOI:
10.1038/cddis.2014.79
[Indexed for MEDLINE]
Free PMC Article

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