EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation.

Abstract

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.

• Authors: Hubin Yin, Chen Zhang, Zongjie Wei, Weiyang He, Ning Xu, Yingjie Xu, Tinghao Li, Ke Ren, Youlin Kuang, Xin Zhu, Fangchao Yuan, Haitao Yu, Xin Gou
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 1 Pg. 39 (01 10 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35013128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• GTPase-Activating Proteins
• RAC1 protein, human
• SHC1 protein, human
• SHCBP1 protein, human
• Shc Signaling Adaptor Proteins
• Src Homology 2 Domain-Containing, Transforming Protein 1
• mgcRacGAP
• Epidermal Growth Factor
• rac1 GTP-Binding Protein

Topics

• Active Transport, Cell Nucleus (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Nucleus (metabolism)
• Cell Proliferation
• Disease Progression
• Epidermal Growth Factor (metabolism, pharmacology)
• GTPase-Activating Proteins (metabolism)
• Humans
• Hydrolysis
• Protein Binding
• Shc Signaling Adaptor Proteins (metabolism)
• Signal Transduction
• Src Homology 2 Domain-Containing, Transforming Protein 1 (metabolism)
• Urinary Bladder Neoplasms (metabolism, pathology)
• rac1 GTP-Binding Protein (metabolism)