title: PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase.
abstract: The tumor suppressor PTEN plays a critical role in the regulation of multiple cellular processes that include survival, cell cycle, proliferation, and apoptosis. PTEN is frequently mutated or deleted in various human cancer cells to promote tumorigenesis. PTEN is regulated by SUMOylation, but the SUMO E3 ligase involved in the SUMOylation of PTEN remains unclear. Here, we demonstrated that PIASxα is a SUMO E3 ligase for PTEN. PIASxα physically interacted with PTEN both in vitro and in vivo. Their interaction depended on the integrity of phosphatase and C2 domains of PTEN and the region of PIASxα comprising residues 134-347. PIASxα enhanced PTEN protein stability by reducing PTEN ubiquitination, whereas the mutation of PTEN SUMO1 conjugation sites neutralized the effect of PIASxα on PTEN protein half-life. Functionally, PIASxα, as a potential tumor suppressor, negatively regulated the PI3K-Akt pathway through stabilizing PTEN protein. Overexpression of PIASxα led to G0/G1 cell cycle arrest, thus triggering cell proliferation inhibition and tumor suppression, whereas PIASxα knockdown or deficiency in catalytic activity abolished the inhibition. Together our studies suggest that PIASxα is a novel SUMO E3 ligase for PTEN, and it positively regulates PTEN protein level in tumor suppression.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.forename: Shuya
authors.initials: S
authors.lastname: Wang
authors.forename: Ningguang
authors.initials: N
authors.lastname: Hu
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Cao
authors.forename: Wengong
authors.initials: W
authors.lastname: Wang
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C501001:PIAS2 protein, human; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI 3-Kinase (PI3K); PIASxα; PTEN; SUMO E3 Ligase; Sumoylation; Tumor; Tumor Inhibition; Ubiquitination