Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family

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• 作者：Wilber Romero-Fernandez^a ; ^{Wilber.Romero-Fernandez@ki.se"" rel=""nofollow} ; Dasiel O. Borroto-Escuela^a ; ^{Dasiel.Borroto-Escuela@ki.se"" rel=""nofollow} ; Alexander O. Tarakanov^b ; Giuseppa Mudó ; ^c ; ^{g.mudo@unipa.it"" rel=""nofollow} ; Manuel Narvaez^d ; ^{mnarvaez@uma.es"" rel=""nofollow} ; Mileidys Pé ; rez-Alea^e ; ^{m.perez@aston.ac.uk"" rel=""nofollow} ; Luigi F. Agnati^f ; ^{luigiagnati@tin.it"" rel=""nofollow} ; Francisco Ciruela^g ; ^{fciruela@ub.edu"" rel=""nofollow} ; Natale Belluardo^c ; ^{n.belluardo@unipa.it"" rel=""nofollow} ; Kjell Fuxe^a ; ^{Kjell.Fuxe@ki.se"" rel=""nofollow}
• 关键词：Fibroblast growth factors ; FGFR1 ; Homodimerization ; BRET ; MAPK
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：17 June 2011
• 年：2011
• 卷：409
• 期：4
• 页码：764-768
• 全文大小：613 K

文摘

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 BRET² 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.