The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for

Stabilization of PTEN by targeting CHIP can be a novel therapeutic approach in cancer regulation.The tumor suppressor, PTEN is key to the regulation ofdiverse cellular processes, making it a prime candidate to betightlyregulated.ThePTENleveliscontrolledinamajorwaybyE3 ligase-mediated degradation through the Ubiquitin-Protea-some System (UPS). Nedd 4-1, XIAP, and WWP2 have beenshown to maintain PTEN turnover. Here, we report that CHIP,the chaperone-associated E3 ligase, induces ubiquitination andregulates the proteasomal turnover of PTEN. It was apparentfrom our findings that PTEN transiently associates with themolecularchaperonesandtherebygetsdivertedtothedegrada-tion pathway through its interaction with CHIP. The TPRdomain of CHIP and parts of the N-terminal domain of PTENarerequiredfortheirinteraction.OverexpressionofCHIPleadsto elevated ubiquitination and a shortened half-life of endoge-nousPTEN.Ontheotherhand,depletionofendogenousCHIPstabilizes PTEN. CHIP is also shown to regulate PTEN-depen-dent transcription presumably through its down-regulation.PTEN shared an inverse correlation with CHIP in human pros-tatecancerpatientsamples,therebytriggeringtheprospectsofamore complex mode of PTEN regulation in cancer.