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PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

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  • Min-Sik Lee

    (College of Life Science and Biotechnology, Yonsei University)

  • Man-Hyung Jeong

    (College of Life Science and Biotechnology, Yonsei University)

  • Hyun-Woo Lee

    (Yonsei University College of Medicine)

  • Hyun-Ji Han

    (College of Life Science and Biotechnology, Yonsei University)

  • Aram Ko

    (College of Life Science and Biotechnology, Yonsei University)

  • Stephen M. Hewitt

    (Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500)

  • Jae-Hoon Kim

    (Gangnam Severance Hospital, Yonsei University College of Medicine
    Institute of Women’s Life Medical Science, Yonsei University College of Medicine)

  • Kyung-Hee Chun

    (Yonsei University College of Medicine)

  • Joon-Yong Chung

    (Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500)

  • Cheolju Lee

    (BRI, Korea Institute of Science and Technology)

  • Hanbyoul Cho

    (Gangnam Severance Hospital, Yonsei University College of Medicine
    Institute of Women’s Life Medical Science, Yonsei University College of Medicine)

  • Jaewhan Song

    (College of Life Science and Biotechnology, Yonsei University)

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.

Suggested Citation

  • 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, 2015. "PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8769
    DOI: 10.1038/ncomms8769
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    Cited by:

    1. Hyunjin Rho & Seungyeon Kim & Seung Up Kim & Jeong Won Kim & Sang Hoon Lee & Sang Hoon Park & Freddy E. Escorcia & Joon-Yong Chung & Jaewhan Song, 2024. "CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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