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

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

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37 Citations (Scopus)

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.

Original language	English
Article number	e1131
Journal	Cell Death and Disease
Volume	5
Issue number	3
DOIs	https://doi.org/10.1038/cddis.2014.79
Publication status	Published - 2014 Mar

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr. Chin Ha Chung, Seoul National University, Republic of Korea, for providing CHIP (−/−) MEF cells and DNA constructs. This research was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120090).

All Science Journal Classification (ASJC) codes

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

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10.1038/cddis.2014.79

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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.",

author = "Ko, {H. R.} and Kim, {C. K.} and Lee, {S. B.} and J. Song and Lee, {K. H.} and Kim, {K. K.} and Park, {K. W.} and Cho, {S. W.} and Ahn, {J. Y.}",

note = "Funding Information: Acknowledgements. We thank Dr. Chin Ha Chung, Seoul National University, Republic of Korea, for providing CHIP (−/−) MEF cells and DNA constructs. This research was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120090).",

year = "2014",

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doi = "10.1038/cddis.2014.79",

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AU - Ko, H. R.

AU - Kim, C. K.

AU - Lee, S. B.

AU - Song, J.

AU - Lee, K. H.

AU - Kim, K. K.

AU - Park, K. W.

AU - Cho, S. W.

AU - Ahn, J. Y.

N1 - Funding Information: Acknowledgements. We thank Dr. Chin Ha Chung, Seoul National University, Republic of Korea, for providing CHIP (−/−) MEF cells and DNA constructs. This research was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120090).

PY - 2014/3

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N2 - 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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P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP

Abstract

Bibliographical note

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UN SDGs

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