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, Jaewhan Song, K. H. Lee, K. K. Kim, K. W. Park, S. W. Cho, J. Y. Ahn

Research output: Contribution to journalArticle

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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 languageEnglish
Article numbere1131
JournalCell Death and Disease
Volume5
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

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Ubiquitin-Protein Ligases
Inositol
Carrier Proteins
Phosphotransferases
Neoplasms
Ubiquitination
Ubiquitin
Proteolysis
Protein Isoforms
Lipids

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Ko, H. R. ; Kim, C. K. ; Lee, S. B. ; Song, Jaewhan ; Lee, K. H. ; Kim, K. K. ; Park, K. W. ; Cho, S. W. ; Ahn, J. Y. / P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP. In: Cell Death and Disease. 2014 ; Vol. 5, No. 3.
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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.",
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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. / Ko, H. R.; Kim, C. K.; Lee, S. B.; Song, Jaewhan; Lee, K. H.; Kim, K. K.; Park, K. W.; Cho, S. W.; Ahn, J. Y.

In: Cell Death and Disease, Vol. 5, No. 3, e1131, 01.01.2014.

Research output: Contribution to journalArticle

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AU - Ko, H. R.

AU - Kim, C. K.

AU - Lee, S. B.

AU - Song, Jaewhan

AU - Lee, K. H.

AU - Kim, K. K.

AU - Park, K. W.

AU - Cho, S. W.

AU - Ahn, J. Y.

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