EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation.
EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation.
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EGF诱导的SHCBP1核转位通过抑制RACGAP1介导的RAC1失活促进膀胱癌进展
DOI：
10.1038/s41419-021-04479-w
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发表时间：
2022-01-10
影响因子：
9
通讯作者：
Gou X
中科院分区：
文献类型：
--
作者：
Yin H;Zhang C;Wei Z;He W;Xu N;Xu Y;Li T;Ren K;Kuang Y;Zhu X;Yuan F;Yu H;Gou X
膀胱癌是一种高度异质性和侵袭性的恶性肿瘤，预后差。EGF/EGFR激活会导致SHC结合蛋白1 （SHCBP1）与SHC适配蛋白1 （SHC1）分离，后者随后易位到细胞核中，并通过多种信号通路促进癌症发展。然而，EGF-SHCBP1轴在膀胱癌进展中的作用仍未被探索。在此，我们报道了SHCBP1在膀胱癌组织和细胞中上调，并伴有细胞质或核定位。释放的SHCBP1在Ser273磷酸化后通过转运进入细胞核响应EGF刺激。SHCBP1的缺失减少了egf诱导的膀胱癌细胞的迁移和侵袭性。机制上，SHCBP1通过氨基酸1 ~ 428的n端结构域与RACGAP1结合，这种相互作用在EGF处理后增强。此外，SHCBP1通过抑制racgap介导的GTP-RAC1失活来促进细胞迁移，而GTP-RAC1的活性是细胞运动不可或缺的。总之，我们证明了EGF-SHCBP1-RACGAP1-RAC1轴是膀胱癌进展的一种新的调控机制，这为对抗膀胱癌提供了一种新的临床治疗策略。
Bladder cancer is a highly heterogeneous and aggressive malignancy with a poor prognosis. EGF/EGFR activation causes the detachment of SHC-binding protein 1 (SHCBP1) from SHC adapter protein 1 (SHC1), which subsequently translocates into the nucleus and promotes cancer development via multiple signaling pathways. However, the role of the EGF-SHCBP1 axis in bladder cancer progression remains unexplored. Herein, we report that SHCBP1 is upregulated in bladder cancer tissues and cells, with cytoplasmic or nuclear localization. Released SHCBP1 responds to EGF stimulation by translocating into the nucleus following Ser273 phosphorylation. Depletion of SHCBP1 reduces EGF-induced cell migration and invasiveness of bladder cancer cells. Mechanistically, SHCBP1 binds to RACGAP1 via its N-terminal domain of amino acids 1 ~ 428, and this interaction is enhanced following EGF treatment. Furthermore, SHCBP1 facilitates cell migration by inhibiting RACGAP-mediated GTP-RAC1 inactivation, whose activity is indispensable for cell movement. Collectively, we demonstrate that the EGF-SHCBP1-RACGAP1-RAC1 axis acts as a novel regulatory mechanism of bladder cancer progression, which offers a new clinical therapeutic strategy to combat bladder cancer.
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DOI：
10.1186/s13046-017-0616-z
发表时间：
2017-10-11
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Peng C;Zhao H;Song Y;Chen W;Wang X;Liu X;Zhang C;Zhao J;Li J;Cheng G;Wu D;Gao C;Wang X
通讯作者：
Wang X
DOI：
10.1083/jcb.200801047
发表时间：
2008-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Michaelson D;Abidi W;Guardavaccaro D;Zhou M;Ahearn I;Pagano M;Philips MR
通讯作者：
Philips MR
DOI：
10.1083/jcb.201204107
发表时间：
2012-09-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bastos RN;Penate X;Bates M;Hammond D;Barr FA
通讯作者：
Barr FA
影响因子：
4
作者：
Jacquemet, Guillaume;Morgan, Mark R.;Humphries, Martin J.
通讯作者：
Humphries, Martin J.
假基因RACGAP1P作为竞争性内源RNA激活RACGAP1/Rho/ERK信号轴促进肝细胞癌早期复发
影响因子：
9
作者：
Wang, Meng-Yao;Chen, Dong-Ping;Liu, Jin-Quan
通讯作者：
Liu, Jin-Quan