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

H R Ko; C K Kim; S B Lee; J Song; K-H Lee; K K Kim; K W Park; S-W Cho; J-Y Ahn

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

Cell Death Dis. 2014 Mar 20;5(3):e1131. doi: 10.1038/cddis.2014.79.

Authors

H R Ko¹, C K Kim¹, S B Lee¹, J Song², K-H Lee³, K K Kim¹, K W Park⁴, S-W Cho⁵, J-Y Ahn¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*
DNA-Binding Proteins
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*
PC12 Cells
Proteasome Endopeptidase Complex / metabolism*
Protein Isoforms
Protein Stability
Proteolysis
RNA Interference
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Rats
Time Factors
Transfection
Tumor Burden
Ubiquitin-Protein Ligases / deficiency
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
src Homology Domains

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
HSP70 Heat-Shock Proteins
Nuclear Proteins
PA2G4 protein, human
Pa2g4 protein, mouse
Protein Isoforms
RNA-Binding Proteins
STUB1 protein, human
Stub1 protein, mouse
Ubiquitin-Protein Ligases
Class Ia Phosphatidylinositol 3-Kinase
Proteasome Endopeptidase Complex