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PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis.

Nature communications (2015-07-18)
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
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.

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