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.
Bibliographical noteFunding 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.
© 2015 Macmillan Publishers Limited. All rights reserved.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)