PIASx{alpha} enhances SUMO1 modification of PTEN as a SUMO E3 ligase [Protein Synthesis and Degradation]

December 16th, 2013 by Wang, W., Chen, Y., Wang, S., Hu, N., Cao, Z., , Tong, T., Zhang, X.

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 the inhibition of cell proliferation and tumorigenesis. Together, our studies suggest that PIASxα is a novel SUMO E3 ligase for PTEN and it positively regulates PTEN protein level in tumor suppression.