biostudies-literatureUnknown22(20)Degnin CRFibroblast 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 cleavageMolecular biology of the cell3861-73https://www.ebi.ac.uk/biostudies/studies/S-EPMC3192865biostudies-literatureLigand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3.PMC3192865Degnin CRHorton WALaederich MBfalseLigand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3.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 cleavage2011-01-01T00:00:00Z2011 Oct2026-04-13T08:39:54.756Z2026-04-07T13:30:32.187ZS-EPMC31928652186559310.1091/mbc.E11-01-0080