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

• Published in: Cell death & disease Vol. 5; no. 3; p. e1131
• Main Authors: Ko, H R, Kim, C K, Lee, S B, Song, J, Lee, K-H, Kim, K K, Park, K W, Cho, S-W, Ahn, J-Y
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 20.03.2014; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Binding Sites; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Glioma - enzymology; Glioma - genetics; Glioma - pathology; HEK293 Cells; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; PC12 Cells; Proteasome Endopeptidase Complex - metabolism; Protein Isoforms; Protein Stability; Proteolysis; Rats; RNA Interference; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; src Homology Domains; Time Factors; Transfection; Tumor Burden; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.79

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.