USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling
USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling
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USP49 通过 FKBP51-AKT 信号传导负向调节肿瘤发生和化疗耐药。
DOI：
10.15252/embj.201695669
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发表时间：
2017-05-15
期刊：
影响因子：
11.4
通讯作者：
Yuan, Jian
中科院分区：
文献类型：
--
作者：
Luo, Kuntian;Li, Yunhui;Yuan, Jian
AKT 通路是介导多种细胞过程的基本信号通路，例如细胞增殖和存活、血管生成和葡萄糖代谢。我们最近报道，亲免蛋白 FKBP51 是一种支架蛋白，可以增强 PHLPP-AKT 相互作用，促进 PHLPP 介导的 AKT Ser473 去磷酸化，负向调节 AKT 激活。然而，FKBP51-PHLPP-AKT 通路的调控仍不清楚。在此，我们报道去泛素酶 USP49 是 AKT 通路的新调节因子。从机制上讲，USP49 去泛素化并稳定 FKBP51，从而增强 PHLPP 去磷酸化 AKT 的能力。此外，USP49 以 FKBP51-AKT 依赖性方式抑制胰腺癌细胞增殖并增强细胞对吉西他滨的反应。临床上，胰腺癌患者中 USP49 表达降低与 FKBP51 表达降低和 AKT 磷酸化增加相关。总体而言，我们的研究结果表明 USP49 是 AKT 通路的新型调节剂，在胰腺癌的肿瘤发生和化疗反应中发挥着关键作用。
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.