ArticleThe Journal of biological chemistry2009
Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoform.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 86 citations in OpenAlex.
- Trial
- Proteome-Wide Analysis of Functional Phosphosites in the FGFR Family of Proteins: Insights from Large-Scale Phosphoproteomic Analysis.Proteomes · 2026Article
- Unraveling the FGFR-RNA splicing axis: Mechanisms, oncogenic crosstalks and innovations for therapeutic purpose.Acta pharmaceutica Sinica. B · 2026Review
- Research on Targeted Therapy for Malignant Tumors of the Biliary Tract.OncoTargets and therapy · 2026Review
- Article
- Clinical Value of Liquid Biopsy in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma During Targeted Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Case report: High-grade serous tubo-ovarian carcinoma withFrontiers in oncology · 2024Article
- Development and disease-specific regulation of RNA splicing in cardiovascular system.Frontiers in cell and developmental biology · 2024Review
- Oncogenic activation revealed by FGFR2 genetic alterations in intrahepatic cholangiocarcinomas.Cell & bioscience · 2023Article
- RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.Cancer discovery · 2023Article
- Bioinformatics analysis of C3 in brain low-grade gliomas as potential therapeutic target and promoting immune cell infiltration.Medical oncology (Northwood, London, England) · 2022Article
- Review
- 2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology.Journal of oncology · 2021Review
- Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis.Journal of experimental & clinical cancer research : CR · 2020Review
- Fibroblast growth factor signalling in osteoarthritis and cartilage repair.Nature reviews. Rheumatology · 2020Review
- Cancer Mutations in FGFR2 Prevent a Negative Feedback Loop Mediated by the ERK1/2 Pathway.Cells · 2019Article
- Alternative Splicing in Angiogenesis.International journal of molecular sciences · 2019Review
- An integrated approach to infer cross-talks between intracellular protein transport and signaling pathways.BMC bioinformatics · 2018Article
- Interplay between FGFR2b-induced autophagy and phagocytosis: role of PLCγ-mediated signalling.Journal of cellular and molecular medicine · 2018Article
- Challenges and future of biomarker tests in the era of precision oncology: Can we rely on immunohistochemistry (IHC) or fluorescenceOncotarget · 2017Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Alternative splice variants of fibroblast growth factor receptor 2 (FGFR2) IIIb, designated C1, C2, and C3, possess progressive reduction in their cytoplasmic carboxyl termini (822, 788, and 769 residues, respectively), with preferential expression of the C2 and C3 isoforms in human cancers. We determined that the progressive deletion of carboxyl-terminal sequences correlated with increasing transforming potency. The highly transforming C3 variant lacks five tyrosine residues present in C1, and we determined that the loss of Tyr-770 alone enhanced FGFR2 IIIb C1 transforming activity. Because Tyr-770 may compose a putative YXXL sorting motif, we hypothesized that loss of Tyr-770 in the 770YXXL motif may cause disruption of FGFR2 IIIb C1 internalization and enhance transforming activity. Surprisingly, we found that mutation of Leu-773 but not Tyr-770 impaired receptor internalization and increased receptor stability and activation. Interestingly, concurrent mutations of Tyr-770 and Leu-773 caused 2-fold higher transforming activity than caused by the Y770F or L773A single mutations, suggesting loss of Tyr and Leu residues of the 770YXXL773 motif enhances FGFR2 IIIb transforming activity by distinct mechanisms. We also determined that loss of Tyr-770 caused persistent activation of FRS2 by enhancing FRS2 binding to FGFR2 IIIb. Furthermore, we found that FRS2 binding to FGFR2 IIIb is required for increased FRS2 tyrosine phosphorylation and enhanced transforming activity by Y770F mutation. Our data support a dual mechanism where deletion of the 770YXXL773 motif promotes FGFR2 IIIb C3 transforming activity by causing aberrant receptor recycling and stability and persistent FRS2-dependent signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.