FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting γ-catenin K63-linked ubiquitylation
FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting γ-catenin K63-linked ubiquitylation
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FBW7 通过促进 γ-catenin K63 泛素化抑制细胞增殖和 G2/M 细胞周期转变
DOI：
10.1016/j.bbrc.2018.01.192
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发表时间：
2018-03-04
影响因子：
3.1
通讯作者：
Yin, Dong
中科院分区：
文献类型：
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作者：
Li, Yu;Hu, Kaishun;Yin, Dong
FBW7是一种E3泛素连接酶，在各种类型的癌症中经常发生突变。作为SCF泛素连接酶复合物的一个组成部分，FBW7通常通过K11或k48连接的泛素化和随后的靶蛋白降解来靶向底物。然而，FBW7在人类癌症中介导不可降解的泛素信号传导中的作用尚不清楚。在本研究中，我们通过TAP-MS（串联亲和纯化-质谱）鉴定了γ -catenin是FBW7的一个新的结合蛋白。FBW7的敲低不影响γ -catenin的稳定性，但显著降低γ -catenin的K63-linked泛素，导致γ -catenin下游基因14-3-3 sigma表达降低。救援实验显示，γ -catenin以k63 -联泛素信号依赖的方式促进14-3-3 sigma的表达。此外，我们发现FBW7与γ -catenin共同抑制G2/M细胞周期转变和细胞增殖。综上所述，我们的研究揭示了FBW7与γ -catenin相关并促进其k63连锁泛素化的新机制，为理解FBW7在抑制G2/M细胞周期转变和肿瘤细胞增殖中的作用提供了新的见解。(C) 2018爱思唯尔公司版权所有。
FBW7 is an E3 ubiquitin ligase and frequently mutated in various types of cancer. As a component of SCF ubiquitin ligase complex, FBW7 usually targets the substrates via K11 or K48-linked ubiquitylation and subsequent degradation of target proteins. Nevertheless, the role of FBW7 in mediating non-degradable ubiquitin signaling remains unknown in human cancers. In this study, we identified gamma-catenin as a new binding protein of FBW7 by TAP-MS (tandem affinity purification-mass spectrum). Knockdown of FBW7 did not affect the stability of gamma-catenin, but significantly reduced the K63-linked ubiquitin of gamma-catenin, resulting in decreased expression of gamma-catenin downstream gene 14-3-3 sigma. Rescue experiment revealed that gamma-catenin promoted the expression of 14-3-3 sigma in a K63-linked ubiquitin signaling dependent manner. Furthermore, we showed that FBW7 cooperated with gamma-catenin to inhibit G2/M cell cycle transition and cell proliferation. Taken together, our study uncovered a novel mechanism that FBW7 associated with gamma-catenin and promoted its K63-linked ubiquitylation, providing new insights in understanding the role of FBW7 in inhibiting G2/M cell cycle transition and tumor cell proliferation. (C) 2018 Elsevier Inc. All rights reserved.