title: PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis.
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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Min-Sik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Man-Hyung
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Aram
authors.initials: A
authors.lastname: Ko
authors.affiliation: Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500, Bethesda, Maryland 20892, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: 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.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Experimental Pathology Laboratory, Center for Cancer Research, National Cancer Institute, NIH MSC 1500, Bethesda, Maryland 20892, USA.
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Chung
authors.affiliation: BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea.
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Hanbyoul
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D054875:Ubiquitination; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D009419:Nerve Tissue Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012261:Ribonucleoproteins; D058570:TOR Serine-Threonine Kinases; C410808:Makorin ring finger protein 1; C546842:MTOR protein, human; C512478:EGFR protein, human; C494929:PTEN protein, human