USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51‐AKT signaling. (31st March 2017)

• Record Type: Journal Article
• Authors: Luo, Kuntian; Li, Yunhui; Yin, Yujiao; Li, Lei; Wu, Chenming; Chen, Yuping; Nowsheen, Somaira; Hu, Qi; Zhang, Lizhi; Lou, Zhenkun; Yuan, Jian
• Is Part Of: EMBO journal. Volume 36:Number 10(2017)
• Page Start: 1434
• Page End: 1446
• Publication Date: 2017-03-31
• Subjects: AKT -- chemoresistance -- deubiquitination -- FKBP51; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201695669
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP‐AKT interaction and facilitate PHLPP‐mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51‐PHLPP‐AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway. Mechanistically, USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP's capability to dephosphorylate AKT. Furthermore, USP49 inhibited pancreatic cancer cell proliferation and enhanced cellular response to gemcitabine in a FKBP51‐AKT‐dependent manner. Clinically, decreased expression of USP49 in patients with pancreatic cancer was associated with decreased FKBP51 expression and increased AKT phosphorylation. Overall, our findings establish USP49 as a novel regulator of AKT pathway with a critical role in tumorigenesis and chemo‐response in pancreatic cancer. Synopsis: The immunophilin scaffold protein FKBP51, which facilitates AKT interaction with and dephosphorylation by PHLPP, is stabilized by deubiquitination, implicating the deubiquitinase USP49 as a new inhibitor of cancer cell proliferation and tumorigenesis. USP49 deubiquitinates and stabilizes the immunophilin FKBP51. FKBP51 stabilization enhances AKT Ser473 dephosphorylation by the phosphatase PHLPP. USP49 negatively regulates pancreatic tumorigenesis in vivo through the FKBP51‐PHLPP‐AKT pathway. USP49 regulates chemotherapeutic responses in pancreatic cancer cells in an AKT‐dependent manner. Abstract : Deubiquitination stabilizes an immunophilin scaffold protein to facilitate AKT dephosphorylation and suppress cancer cell proliferation.