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USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51‐AKT signaling
Author(s) -
Luo Kuntian,
Li Yunhui,
Yin Yujiao,
Li Lei,
Wu Chenming,
Chen Yuping,
Nowsheen Somaira,
Hu Qi,
Zhang Lizhi,
Lou Zhenkun,
Yuan Jian
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695669
Subject(s) - protein kinase b , biology , cancer research , microbiology and biotechnology , phosphorylation , signal transduction , carcinogenesis , pi3k/akt/mtor pathway , proto oncogene proteins c akt , cancer , genetics
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 FKBP 51 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 FKBP 51‐ PHLPP ‐ AKT pathway remains unclear. Here we report that a deubiquitinase, USP 49, is a new regulator of the AKT pathway. Mechanistically, USP 49 deubiquitinates and stabilizes FKBP 51, which in turn enhances PHLPP 's capability to dephosphorylate AKT . Furthermore, USP 49 inhibited pancreatic cancer cell proliferation and enhanced cellular response to gemcitabine in a FKBP 51‐ AKT ‐dependent manner. Clinically, decreased expression of USP 49 in patients with pancreatic cancer was associated with decreased FKBP 51 expression and increased AKT phosphorylation. Overall, our findings establish USP 49 as a novel regulator of AKT pathway with a critical role in tumorigenesis and chemo‐response in pancreatic cancer.