title: Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1.
abstract: 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.
authors.affiliation: Centre for Neuroendocrinology, University College London Medical School, Royal Free Campus, London NW32PF. y.hu@medsch.ucl.ac.uk
authors.forename: Youli
authors.initials: Y
authors.lastname: Hu
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.forename: Paul
authors.initials: P
authors.lastname: Travers
authors.forename: Steven
authors.initials: S
authors.lastname: Cadman
authors.forename: Erhard
authors.initials: E
authors.lastname: Hohenester
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Pierre-Marc
authors.initials: PM
authors.lastname: Bouloux
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D002522:Chlorocebus aethiops; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; C076266:ANOS1 protein, human; C496348:FGFR1 protein, human; C496365:FGFR3 protein, human
references.citation: Science. 1993 Mar 26;259(5103):1918-21
references.pmid: 8456318
references.citation: Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9
references.pmid: 16764984
references.citation: Endocrinology. 2008 Oct;149(10):4997-5003
references.pmid: 18566132
references.citation: J Biol Chem. 2006 Nov 17;281(46):35208-16
references.pmid: 17005551
references.citation: BMC Genet. 2006 Oct 11;7:47
references.pmid: 17034626
references.citation: J Mol Biol. 2008 Mar 21;377(2):524-34
references.pmid: 18261743
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):935-40
references.pmid: 14732692
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6346-51
references.pmid: 11983919
references.citation: J Biol Chem. 2006 Dec 8;281(49):37302-10
references.pmid: 17040907
references.citation: Biochem J. 2004 Dec 15;384(Pt 3):495-505
references.pmid: 15324302
references.citation: J Biol Chem. 2008 May 9;283(19):13001-8
references.pmid: 18281281
references.citation: EMBO Rep. 2007 Dec;8(12):1162-9
references.pmid: 17975556
references.citation: Structure. 2003 Jun;11(6):691-701
references.pmid: 12791257
references.citation: Mol Cell. 2000 Sep;6(3):743-50
references.pmid: 11030354
references.citation: Cardiovasc Res. 2003 Jan;57(1):8-19
references.pmid: 12504809
references.citation: Cell. 1999 Sep 3;98(5):641-50
references.pmid: 10490103
references.citation: Hum Mol Genet. 2004 Nov 15;13(22):2781-91
references.pmid: 15471890
references.citation: J Biol Chem. 2002 Jan 25;277(4):2444-53
references.pmid: 11714710
references.citation: J Mol Biol. 2005 Jul 15;350(3):553-70
references.pmid: 15949815
references.citation: Curr Biol. 1999 Nov 18;9(22):1343-6
references.pmid: 10574766
references.citation: Nature. 1991 Oct 10;353(6344):529-36
references.pmid: 1922361
references.citation: Mol Endocrinol. 2005 Jan;19(1):225-36
references.pmid: 15459253
references.citation: J Neuroendocrinol. 2008 Feb;20(2):141-63
references.pmid: 18034870
references.citation: J Clin Invest. 2007 Feb;117(2):457-63
references.pmid: 17235395
references.citation: Sex Dev. 2008;2(4-5):181-93
references.pmid: 18987492
references.citation: Mol Cell Neurosci. 2008 Mar;37(3):528-36
references.pmid: 18222703
references.citation: Nat Cell Biol. 2004 Jan;6(1):38-44
references.pmid: 14688794
references.citation: Nature. 2000 Oct 26;407(6807):1029-34
references.pmid: 11069186
references.citation: Mol Cell Neurosci. 2006 Sep;33(1):2-14
references.pmid: 16876430
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):107-37
references.pmid: 15863029
references.citation: J Neurosci. 2004 Nov 17;24(46):10384-92
references.pmid: 15548653
references.citation: J Neurosci. 1995 Jun;15(6):4382-94
references.pmid: 7790915
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):205-13
references.pmid: 15863035
references.citation: J Cell Biol. 2003 Nov 10;163(3):637-48
references.pmid: 14610064
references.citation: Cell. 1991 Oct 18;67(2):423-35
references.pmid: 1913827
references.citation: J Mol Biol. 2004 Jun 11;339(4):821-34
references.pmid: 15165853
references.citation: Biochem J. 2001 Aug 1;357(Pt 3):647-59
references.pmid: 11463336
references.citation: Endocrinology. 2004 Aug;145(8):3830-9
references.pmid: 15117872
references.citation: FEBS Lett. 2006 Jun 12;580(14):3386-90
references.pmid: 16709412
references.citation: Nat Cell Biol. 2002 Feb;4(2):165-9
references.pmid: 11802164
references.citation: Cancer Res. 2003 Oct 1;63(19):6237-43
references.pmid: 14559809
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49
references.pmid: 15863030
references.citation: Nat Genet. 2003 Apr;33(4):463-5
references.pmid: 12627230
references.citation: Curr Opin Struct Biol. 2005 Oct;15(5):506-16
references.pmid: 16154740
references.citation: Neuron. 1997 Feb;18(2):231-42
references.pmid: 9052794
references.citation: Cell. 2000 May 12;101(4):413-24
references.pmid: 10830168
references.citation: Mol Cell Neurosci. 2000 Oct;16(4):283-95
references.pmid: 11085868
references.citation: Science. 1991 Jan 4;251(4989):72-5
references.pmid: 1846048