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Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1.

TitleNovel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1.
Publication TypeJournal Article
Year of Publication2009
AuthorsHu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim S-H, Bouloux P-M
JournalJ Biol Chem
Date Published2009 Oct 23
KeywordsAnimals, Cell Membrane, Cercopithecus aethiops, Chemotaxis, COS Cells, Extracellular Matrix Proteins, Fibroblast Growth Factor 2, Heparitin Sulfate, Humans, Multiprotein Complexes, Nerve Tissue Proteins, Neurons, Protein Binding, Protein Structure, Tertiary, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3, Signal Transduction

Activation of fibroblast growth factor (FGF) signaling is initiated by a multiprotein complex formation between FGF, FGF receptor (FGFR), and heparan sulfate proteoglycan on the cell membrane. Cross-talk with other factors could affect this complex assembly and modulate the biological response of cells to FGF. We have previously demonstrated that anosmin-1, a glycosylated extracellular matrix protein, interacts with the FGFR1 signaling complex and enhances its activity in an IIIc isoform-specific and HS-dependent manner. The molecular mechanism of anosmin-1 action on FGFR1 signaling, however, remains unknown. Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. This interaction involves domains in the N terminus of anosmin-1 (cysteine-rich region, whey acidic protein-like domain and the first fibronectin type III domain) and the D2-D3 extracellular domains of FGFR1. In contrast, anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. We also show that FGFR1-bound anosmin-1, although capable of binding to FGF2 alone, cannot bind to a FGF2.heparin complex, thus preventing FGFR1.FGF2.heparin complex formation. By contrast, heparin-bound anosmin-1 binds to pre-formed FGF2.FGFR1 complex, generating an anosmin-1.FGFR1.FGF2.heparin complex. Furthermore, a functional interaction between anosmin-1 and the FGFR1 signaling complex is demonstrated by immunofluorescence co-localization and Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. Our study provides molecular and cellular evidence for a modulatory action of anosmin-1 on FGFR1 signaling, whereby binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1.FGF2.heparin complex.

Alternate JournalJ. Biol. Chem.
PubMed ID19696444
PubMed Central IDPMC2785620
Grant List083942 / / Wellcome Trust / United Kingdom
BB/F007167/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom