title: Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1.
abstract: Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in the circulation and in vascular basement membranes. However, the process of FGFR1 ectodomain release from the plasma membrane is not known. Here we report that the 72-kDa gelatinase A (matrix metalloproteinase type 2, MMP2) can hydrolyze the Val368-Met369 peptide bond of the FGFR1 ectodomain, eight amino acids upstream of the transmembrane domain, thus releasing the entire extracellular domain. Similar results were obtained regardless of whether FGF was first bound to the receptor or not. The action of MMP2 abolished binding of FGF to an immobilized recombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovary cells overexpressing FGFR1 The released recombinant FGFR1 ectodomain was able to bind FGF after MMP2 cleavage, suggesting that the cleaved soluble receptor maintained its FGF binding capacity. The activity of MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and was inhibited by tissue inhibitor of metalloproteinase type 2. These studies demonstrate that FGFR1 may be a specific target for MMP2 on the cell surface, yielding a soluble FGF receptor that may modulate the mitogenic and angiogenic activities of FGF.
authors.affiliation: Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Levi
authors.forename: R
authors.initials: R
authors.lastname: Fridman
authors.forename: H Q
authors.initials: HQ
authors.lastname: Miao
authors.forename: Y S
authors.initials: YS
authors.lastname: Ma
authors.forename: A
authors.initials: A
authors.lastname: Yayon
authors.forename: I
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism*; D008715:Methionine; D051379:Mice; D008969:Molecular Sequence Data; D011506:Proteins / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D019716:Tissue Inhibitor of Metalloproteinase-2; D014162:Transfection; D014633:Valine
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D019716:Tissue Inhibitor of Metalloproteinase-2; D008715:Methionine; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D014633:Valine