PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

Min Sik Lee, Man Hyung Jeong, Hyun Woo Lee, Hyun Ji Han, Aram Ko, Stephen M. Hewitt, Jae Hoon Kim, Kyung Hee Chun, Joon Yong Chung, Cheolju Lee, Hanbyoul Cho, Jaewhan Song

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.

Original languageEnglish
Article number7769
JournalNature communications
Volume6
DOIs
Publication statusPublished - 2015 Jul 17

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phosphatases
Ubiquitination
destabilization
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Chemical activation
activation
Post Translational Protein Processing
Uterine Cervical Neoplasms
cancer
phosphorylation
Phosphorylation
positive feedback
Ubiquitin-Protein Ligases
mutations
Tensins
Survival Rate
Stabilization
stabilization
retarding

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lee, Min Sik ; Jeong, Man Hyung ; Lee, Hyun Woo ; Han, Hyun Ji ; Ko, Aram ; Hewitt, Stephen M. ; Kim, Jae Hoon ; Chun, Kyung Hee ; Chung, Joon Yong ; Lee, Cheolju ; Cho, Hanbyoul ; Song, Jaewhan. / PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. In: Nature communications. 2015 ; Vol. 6.
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abstract = "The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.",
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Lee, MS, Jeong, MH, Lee, HW, Han, HJ, Ko, A, Hewitt, SM, Kim, JH, Chun, KH, Chung, JY, Lee, C, Cho, H & Song, J 2015, 'PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis', Nature communications, vol. 6, 7769. https://doi.org/10.1038/ncomms8769

PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. / Lee, Min Sik; Jeong, Man Hyung; Lee, Hyun Woo; Han, Hyun Ji; Ko, Aram; Hewitt, Stephen M.; Kim, Jae Hoon; Chun, Kyung Hee; Chung, Joon Yong; Lee, Cheolju; Cho, Hanbyoul; Song, Jaewhan.

In: Nature communications, Vol. 6, 7769, 17.07.2015.

Research output: Contribution to journalArticle

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AU - Lee, Min Sik

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AU - Han, Hyun Ji

AU - Ko, Aram

AU - Hewitt, Stephen M.

AU - Kim, Jae Hoon

AU - Chun, Kyung Hee

AU - Chung, Joon Yong

AU - Lee, Cheolju

AU - Cho, Hanbyoul

AU - Song, Jaewhan

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