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 () and Jaewhan Song ()
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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
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
Jaewhan Song: College of Life Science and Biotechnology, Yonsei University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8769

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