PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26183061.
- Also identified by DOI 10.1038/ncomms8769 and PMC identifier 4518267.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Carcinoma
- Gene Expression Regulation, Neoplastic
- Nerve Tissue Proteins
- PTEN Phosphohydrolase
- Phosphatidylinositol 3-Kinases
- Proto-Oncogene Proteins c-akt
- Ribonucleoproteins
- Uterine Cervical Neoplasms
- Uterine Cervical Dysplasia