ArticleMolecular biology of the cell2011
Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3.
Article in Molecular biology of the cell, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 41 citations in OpenAlex.
- Fibroblast growth factor signaling in axons: from development to disease.Cell communication and signaling : CCS · 2023Review
- Glycosylation of FGFR4 in cholangiocarcinoma regulates receptor processing and cancer signaling.Journal of cellular biochemistry · 2022Article
- Review
- Proteolytic Cleavage of Receptor Tyrosine Kinases.Biomolecules · 2021Review
- Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.Current osteoporosis reports · 2019Review
- Review
- Targeting Cellular Trafficking of Fibroblast Growth Factor Receptors as a Strategy for Selective Cancer Treatment.Journal of clinical medicine · 2018Review
- VEGF-A selectively inhibits FLT1 ectodomain shedding independent of receptor activation and receptor endocytosis.American journal of physiology. Cell physiology · 2018Article
- Genome-wide screen of gamma-secretase-mediated intramembrane cleavage of receptor tyrosine kinases.Molecular biology of the cell · 2017Article
- SheddomeDB: the ectodomain shedding database for membrane-bound shed markers.BMC bioinformatics · 2017Review
- Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases.The FEBS journal · 2015Review
- Fgf9 inhibition of meiotic differentiation in spermatogonia is mediated by Erk-dependent activation of Nodal-Smad2/3 signaling and is antagonized by Kit Ligand.Cell death & disease · 2015Article
- Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations.Blood · 2014Article
- Receptor tyrosine kinases in the nucleus.Cold Spring Harbor perspectives in biology · 2013Review
- PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment.Journal of lipid research · 2013Article
- Fibroblast growth factor receptor 3 is highly expressed in rarely dividing human type A spermatogonia.Histochemistry and cell biology · 2012Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fibroblast growth factor receptor 3 (FGFR3) is a major negative regulator of bone growth that inhibits the proliferation and differentiation of growth plate chondrocytes. Activating mutations of its c isoform cause dwarfism in humans; somatic mutations can drive oncogenic transformation in multiple myeloma and bladder cancer. How these distinct activities arise is not clear. FGFR3 was previously shown to undergo proteolytic cleavage in the bovine rib growth plate, but this was not explored further. Here, we show that FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3. The ectodomain is proteolytically cleaved (S1) in response to ligand-induced receptor activation, but unlike most RIP target proteins, it requires endocytosis and does not involve a metalloproteinase. S1 cleavage generates a C-terminal domain fragment that initially remains anchored in the membrane, is phosphorylated, and is spatially distinct from the intact receptor. Ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus. We identify the S1 cleavage site and show that γ-secretase mediates the S2 cleavage event. In this way we demonstrate a mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease.
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