Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

• Published in: The Journal of biological chemistry 2009-10, Vol.284 (43), p.29905-29920
• Main Authors: Hu, Youli, Guimond, Scott E., Travers, Paul, Cadman, Steven, Hohenester, Erhard, Turnbull, Jeremy E., Kim, Soo-Hyun, Bouloux, Pierre-Marc
• Format: Article
• Language: English
• Subjects: Animals; Cell Membrane - genetics; Cell Membrane - metabolism; Chemotaxis - physiology; Chlorocebus aethiops; COS Cells; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Heparitin Sulfate - genetics; Heparitin Sulfate - metabolism; Humans; Molecular Basis of Cell and Developmental Biology; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - cytology; Neurons - metabolism; Protein Binding - physiology; Protein Structure, Tertiary - physiology; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Signal Transduction - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.049155

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.