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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.

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


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.

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