title: Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family.
abstract: Fibroblast growth factor receptor 1 (FGFR1) is known to be activated by homodimerization in the presence of both the FGF agonist ligand and heparan sulfate glycosaminoglycan. FGFR1 homodimers in turn trigger a variety of downstream signaling cascades via autophosphorylation of tyrosine residues in the cytoplasmic domain of FGFR1. By means of Bioluminescence Energy Resonance Transfer (BRET) as a sign of FGFR1 homodimerization, we evaluated in HEK293T cells the effects of all known FGF agonist ligands on homodimer formation. A significant correlation between BRET(2) signaling and ERK1/2 phosphorylation was observed, leading to a further characterization of the binding and signaling properties of the FGF subfamilies. FGF agonist ligand-FGFR1 binding interactions appear as the main mechanism for the control of FGFR1 homodimerization and MAPK signaling which demonstrated a high correlation. The bioinformatic analysis demonstrates the interface of the two pro-triplets SSS (Ser-Ser-Ser) and YGS (Tyr-Gly-Ser) located in the extracellular and intracellular domain of the FGFR1. These pro-triplets are postulated participate in the FGFR1 homodimerization interface interaction. The findings also reveal that FGF agonist ligands within the same subfamily of the FGF gene family produced similar increases in FGFR1 homodimer formation and MAPK signaling. Thus, the evolutionary relationship within this gene family appears to have a distinct functional relevance.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Wilber.Romero-Fernandez@ki.se
authors.forename: Wilber
authors.initials: W
authors.lastname: Romero-Fernandez
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Tarakanov
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Mudó
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.forename: Mileidys
authors.initials: M
authors.lastname: Pérez-Alea
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Natale
authors.initials: N
authors.lastname: Belluardo
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D005346:Fibroblast Growth Factors / Q000819:agonists*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D057809:HEK293 Cells; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D055503:Protein Multimerization; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051496:Receptor, Fibroblast Growth Factor, Type 1; C496348:FGFR1 protein, human; C535150:MAPK1 protein, human