Journal Article

PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

Lee, Min-Sik, Lee, Hyun-Woo, Chung, Joon-Yong, Ko, Aram, Song, Jaewhan, Cho, Hanbyoul, Han, Hyun-Ji, Hewitt, Stephen M., Chun, Kyung-Hee, Kim, Jae-Hoon, Lee, Cheolju, Jeong, Man-Hyung

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 1-Phosphatidylinositol 3-kinase / 13/1 / 13/106 / 13/109 / 13/51 / 13/89 / 13/95 / 42/89 / 631/80/458/582 / 631/80/86 / 64/60 / 692/420/755 / 692/699/67/1517/1371 / 82/1 / 82/80 / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / AKT protein / Cancer / Carcinogenesis - genetics / Carcinoma - genetics / Carcinoma - metabolism / Carcinoma - pathology / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Cell Line, Tumor / Cell Movement / Cervical cancer / Cervical Intraepithelial Neoplasia - genetics / Cervical Intraepithelial Neoplasia - metabolism / Cervix / Degradation / Destabilization / Epidermal growth factor receptors / Feedback, Physiological / Female / Gene Expression Regulation, Neoplastic / HeLa Cells / Homology / Humanities and Social Sciences / Humans / Immunohistochemistry / In Vitro Techniques / multidisciplinary / Mutation / Nerve Tissue Proteins - metabolism / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Phosphoproteins / Phosphorylation / Post-translation / Prognosis / Protein Processing, Post-Translational / Proto-Oncogene Proteins c-akt - metabolism / PTEN Phosphohydrolase - genetics / PTEN Phosphohydrolase - metabolism / PTEN protein / Receptor, Epidermal Growth Factor - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Ribonucleoproteins - metabolism / Science / Survival / Tensin / TOR Serine-Threonine Kinases - metabolism / Translation / Ubiquitin-protein ligase / Ubiquitination / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - metabolism