title: P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP.
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.
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: H R
authors.initials: HR
authors.lastname: Ko
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: C K
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Anatomy, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: K K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Korea.
authors.forename: K W
authors.initials: KW
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: S-W
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Ahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020033:Protein Isoforms; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D009687:Nuclear Proteins; C101633:PA2G4 protein, human; C095938:Pa2g4 protein, mouse; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D046988:Proteasome Endopeptidase Complex