ArticleJournal of translational medicine2021
Src is essential for the endosomal delivery of the FGFR4 signaling complex in hepatocellular carcinoma.
Article in Journal of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 8 citations in OpenAlex.
- The role of FGF19-FGFR4 signaling pathway in liver health and disease: Guardian or destroyer.Genes & diseases · 2026Review
- Review
- Endosomes as central hubs of interorganellar communication and cellular homeostasis.Protein & cell · 2026Review
- Targeting SRC to mediate solasonine's anti-cancer activity in hepatocellular carcinoma and its potential for multi-cancer therapy.Frontiers in oncology · 2026Article
- Cytotoxic and senescence-inducing effects of BLU554 in pancreatic ductal adenocarcinoma: an in vitro study.BMC cancer · 2025Article
- Review
- FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC.Theranostics · 2023Article
- Integrated UPLC-Q-TOF-MS/MS and Network Pharmacology Approach to Investigating the Metabolic Profile of Marein ofEvidence-based complementary and alternative medicine : eCAM · 2022Article
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
backgroundHepatocytes usually express fibroblast growth factor receptor 4 (FGFR4), but not its ligand, fibroblast growth factor 19 (FGF19). A subtype of hepatocellular carcinoma (HCC) expresses FGF19, which activates the FGFR4 signaling pathway that induces cell proliferation. FGFR4 inhibitors that target this mechanism are under clinical development for the treatment of HCCs with FGF19 amplification or FGFR4 overexpression. Src plays an essential role in the FGFR1 and FGFR2 signaling pathways. However, it is yet to be understood whether Src has any role in the FGF19-FGFR4 pathway in HCCs. In this study, we aimed to elucidate the role of Src in the FGF19-FGFR4 axis in HCC.
methods3 HCC cell lines expressing both FGF19 and FGFR4 were selected. The expression of each protein was suppressed by siRNA treatment, and the activity-regulating relationship between FGFR4 and Src was investigated by westernblot. Co-immunoprecipitation was performed using the FGFR4 antibody to identify the endosomal complex formation and receptor endocytosis. The intracellular migration pathways of the endosomal complex were observed by immuno-fluorescence and nuclear co-immunoprecipitation. Dasatinib and BLU9931 were used for cytotoxicity comparison.
resultsFGFR4 modulates the activity of Src and Src modulates the expression of FGFR4, showing a mutual regulatory relationship. FGFR4 activated by FGF19 formed an endosomal complex with Src and STAT3 and moved to the nucleus. However, when Src was suppressed, the formation of the endosomal complex was not observed. FGFR4 was released from the complex transferred into the nucleus and the binding of Src and STAT3 was maintained. Dasatinib showed cytotoxic results comparable to BLU9931. The results of our study demonstrated that Src is essential for the nuclear transport of STAT3, as it induces the endosomal delivery of FGFR4 in FGF19-expressing HCC cell lines.
conclusionsWe found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.
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