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 journalArticlepeer-review

88 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

Bibliographical note

Funding Information:
This work was supported by the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (A121387), the National Cancer Center, Korea (NCC-1420300), the National Research Foundation of Korea (NRF-2013H1A8A1004182) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M.-S.L. was a fellowship awardee by the Brain Korea 21 (BK21) Program.

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

All Science Journal Classification (ASJC) codes

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

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