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.
Highlights
The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification
PTEN is a major tumour suppressor that antagonizes growth factor-stimulated PI3K/AKT signalling by converting PIP3 to PIP2
We identified a novel negative regulatory mechanism of PTEN involving epidermal growth factor (EGF)-dependent PI3K/AKT activation
Summary
The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. A potent inhibitor of the PI3K/AKT pathway is PTEN (phosphatase and tensin homologue), a tumour suppressor that is highly mutated or deleted in various human cancers[1,2,3,4]. We demonstrate that a growth factor-activated PI3K/AKT pathway suppresses PTEN via MKRN1-mediated ubiquitination and degradation. The positive relationship between these posttranslational regulatory pathways and clinical evidence is confirmed by analysis of samples from cervical cancer patients Supporting these observations, xenografts and biochemical analyses indicate inverse correlations between PTEN and the PI3K/AKT-activated MKRN1 axis. These findings suggest a pathway for PI3K/AKT signalling in the regulation of PTEN
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