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

• Published in: The Journal of biological chemistry Vol. 287; no. 19; pp. 15996 - 16006
• Main Authors: Ahmed, Syed Feroj, Deb, Satamita, Paul, Indranil, Chatterjee, Anirban, Mandal, Tapashi, Chatterjee, Uttara, Ghosh, Mrinal K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Cell Line, Tumor; CHIP (Stub1); E3 Ubiquitin Ligase; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; HeLa Cells; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Immunoprecipitation; Microscopy, Fluorescence; Molecular Chaperone; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Mutation; Proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Synthesis and Degradation; Proteolysis; Pten; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; RNA Interference; Transfection; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Molecular Chaperone; E3 Ubiquitin Ligase; Ubiquitination; Pten; CHIP (Stub1); Proteasome
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.321083

The tumor suppressor, PTEN is key to the regulation of diverse cellular processes, making it a prime candidate to be tightly regulated. The PTEN level is controlled in a major way by E3 ligase-mediated degradation through the Ubiquitin-Proteasome System (UPS). Nedd 4-1, XIAP, and WWP2 have been shown to maintain PTEN turnover. Here, we report that CHIP, the chaperone-associated E3 ligase, induces ubiquitination and regulates the proteasomal turnover of PTEN. It was apparent from our findings that PTEN transiently associates with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand, depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTEN-dependent transcription presumably through its down-regulation. PTEN shared an inverse correlation with CHIP in human prostate cancer patient samples, thereby triggering the prospects of a more complex mode of PTEN regulation in cancer. Background: PTEN is targeted by multiple E3 ligases but that does not clearly decipher the rigid control of its level and activity. Results: CHIP interacts with PTEN and promotes its proteasomal degradation. Conclusion: CHIP acts as a bridge between the chaperone system and the degradation machinery for PTEN. Significance: Stabilization of PTEN by targeting CHIP can be a novel therapeutic approach in cancer regulation.