PIASxα enhances SUMO1 modification of PTEN as a SUMO E3 ligase*

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, while 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 triggered 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. PTEN (phosphatase and tensin homologue deleted on chromosome TEN) (1) is a well-defined tumor suppressor that plays a critical role in multiple cellular processes, such as cell proliferation, apoptosis, cell cycle arrest and genomic stability maintenance (2-7). PTEN is reduced in expression, deleted or mutated with high frequency in various types of human cancers and is considered to function as a tumor suppressor (8, 9). The classic function of PTEN is to inhibit the PI3K (phosphatidylinositol http://www.jbc.org/cgi/doi/10.1074/jbc.M113.508515 The latest version is at JBC Papers in Press. Published on December 16, 2013 as Manuscript M113.508515 Copyright 2013 by The American Society for Biochemistry and Molecular Biology, Inc. by gest on O cber 0, 2017 hp://w w w .jb.org/ D ow nladed from