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PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

Min-Sik Lee1, Man-Hyung Jeong1, Hyun-Woo Lee2

  • 1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.

Nature Communications
|July 18, 2015
PubMed

Insights

Epidermal Growth Factor Receptor (EGFR) and PI3K/AKT signaling pathways promote cervical cancer progression by destabilizing phosphatase and tensin homologue (PTEN) through MKRN1 E3 ligase. This pathway correlates with reduced patient survival rates.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Post-translational modifications are known to suppress phosphatase and tensin homologue (PTEN) activity, but the precise mechanisms and physiological relevance remain largely undefined.
  • Understanding PTEN regulation is crucial in cervical cancer, where its dysregulation is implicated in tumorigenesis.

Purpose of the Study:

  • To elucidate the mechanism by which post-translational modifications lead to PTEN suppression in cervical cancer.
  • To investigate the role of Epidermal Growth Factor Receptor (EGFR) and PI3K/AKT signaling in PTEN destabilization.
  • To determine the clinical significance of these molecular events in cervical cancer patient survival.

Main Methods:

  • Utilized molecular biology techniques to investigate protein-protein interactions and degradation pathways.
  • Employed Western blotting and immunoprecipitation assays to assess protein levels and modifications.
  • Analyzed patient data to correlate molecular markers with clinical outcomes.

Main Results:

  • Demonstrated that Epidermal Growth Factor Receptor (EGFR) or oncogenic PI3K mutation-mediated AKT activation induces PTEN destabilization in cervical cancer.
  • Identified MKRN1 E3 ligase as essential for EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN.
  • Showed that AKT-mediated phosphorylation stabilizes MKRN1, facilitating PTEN degradation.
  • Observed that high pAKT and MKRN1 expression in cervical cancer patients correlates with low PTEN protein levels and reduced 5-year survival rates.

Conclusions:

  • PI3K/AKT signaling pathways create a positive-feedback loop by suppressing PTEN function through MKRN1-mediated degradation.
  • The EGFR/AKT/MKRN1/PTEN axis represents a critical regulatory mechanism in cervical cancer.
  • Targeting this pathway holds potential for improving therapeutic strategies and patient outcomes in cervical cancer.

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