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.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…A recent study has shown that the adaptor protein RacGAP1 inactivated GTP-bound Rac1 in bladder cancer, but the activation was inhibited by protein SHCBP1 (SHC-binding protein 1), which is a regulator of EGF (epidermal growth factor). Via this relay, SHCBP1 can inactivate Rac1 and promote bladder cancer progression [ 83 ]. The EGF/EGFR ligand/receptor couple is frequently overexpressed in bladder cancers, with squamous bladder cancers qualified as being EGFR-addicted [ 84 ].…”

Characterization of SHCBP1 to prognosis and immunological landscape in pan-cancer: novel insights to biomarker and therapeutic targets

“…The expression of SHCBP1 was associated with lymph node metastasis in glioma, and patients with over-expressed SHCBP1 had a poor prognosis [ 28 ]. Moreover, the knockout of SHCBP1 reduced the migration and invasion ability in EGF-induced bladder cancer cells [ 11 ]. In addition, SHCBP1 plays an important role in FGF, NF-κB, MAPK/ERK, PI3K/AKT, and TGF-β1/Smad signaling, as well as participating in T cell development and downstream transduction regulation [ 7 ].…”

“…SHCBP1 expression is highly expressed mainly in hyperplastic tissues and cells, suggesting that it is involved in physiological roles and pathological changes in the organism [ 9 ]. Emerging studies have demonstrated that SHCBP1 was up-regulated in several cancers, including breast [ 10 ], bladder [ 11 ], and gastric cancer [ 12 ]. Aberrant expression of SHCBP1 is involved in the occurrence, development, metastasis and prognosis of cancer, suggesting that SHCBP1 has potential value in terms of biomarkers and therapeutic targets [ 13 ].…”

Targeted therapies in bladder cancer: signaling pathways, applications, and challenges

“…EGF/EGFR activation results in the separation of SHC-binding protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which then translocates to the nucleus and promotes cancer development via multiple signaling pathways. 172 Yin et al 173 identified the EGF-SHCBP1-RACGAP1-RAC1 axis, revealing that SHCBP1 is upregulated in the tissues and cells of BC. Following Ser273 phosphorylation, the released SHCBP1 responds to EGF stimulation by transferring it to the nucleus.…”

“…169,188 (ii) The identification of new therapeutic targets has lagged: most of the studies did not explore the upstream targets, mainly downstream of the classic TKI targets. 173,187 (iii) Trials on the anti-BC activities of smallmolecule natural drugs have stagnated in the preclinical stages. Most of the activity studies of small molecule natural drugs are limited to effects on conventional signaling pathways.…”