title: The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation.
abstract: 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.
authors.affiliation: Signal Tranduction in Cancer and Stem Cells Laboratory, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4 Raja S C Mullick Road, Kolkata, 700032, West Bengal, India.
authors.forename: Syed Feroj
authors.initials: SF
authors.lastname: Ahmed
authors.forename: Satamita
authors.initials: S
authors.lastname: Deb
authors.forename: Indranil
authors.initials: I
authors.lastname: Paul
authors.forename: Anirban
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Tapashi
authors.initials: T
authors.lastname: Mandal
authors.forename: Uttara
authors.initials: U
authors.lastname: Chatterjee
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Ghosh
mesh_terms: D045744:Cell Line, Tumor; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D049452:Green Fluorescent Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; D046988:Proteasome Endopeptidase Complex