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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.
Mutations and post-translational modifications of the PI3K/AKT pathway inhibitor PTEN are a feature of many cancers, but these have not been associated with cervical cancer. Here, the authors identify a PI3K/AKT-mediated ubiquitination degradation pathway of PTEN that occurs in patients with cervical cancer.
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Details
1 College of Life Science and Biotechnology, Yonsei University, Department of Biochemistry, Seoul, Republic of Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454)
2 Yonsei University College of Medicine, Department of Biochemistry and Molecular Biology, Seoul, Republic of Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454)
3 Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500, Bethesda, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129)
4 Gangnam Severance Hospital, Yonsei University College of Medicine, Department of Obstetrics and Gynecology, Seoul, Republic of Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454)
5 BRI, Korea Institute of Science and Technology, Seoul, Korea (GRID:grid.35541.36) (ISNI:0000000121053345)