PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

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

doi:10.1038/ncomms8769

PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

Nat Commun. 2015 Jul 17:6:7769. doi: 10.1038/ncomms8769.

Authors

Affiliations

¹ Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
² Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
³ Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500, Bethesda, Maryland 20892, USA.
⁴ 1] Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Republic of Korea [2] Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
⁵ BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
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
ErbB Receptors / metabolism
Feedback, Physiological
Female
Gene Expression Regulation, Neoplastic*
HeLa Cells
Humans
Immunohistochemistry
In Vitro Techniques
Mutation
Nerve Tissue Proteins / metabolism*
PTEN Phosphohydrolase / genetics*
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoproteins
Phosphorylation
Prognosis
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleoproteins / metabolism*
TOR Serine-Threonine Kinases / metabolism
Ubiquitination
Uterine Cervical Dysplasia / genetics*
Uterine Cervical Dysplasia / metabolism
Uterine Cervical Neoplasms / genetics*
Uterine Cervical Neoplasms / metabolism

Substances

Makorin ring finger protein 1
Nerve Tissue Proteins
Phosphoproteins
Ribonucleoproteins
MTOR protein, human
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
PTEN protein, human