TY - JOUR
T1 - Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family
AU - Romero-fernandez, Wilber
AU - Borroto-escuela, Dasiel O.
AU - Tarakanov, Alexander O.
AU - Mudó, Giuseppa
AU - Narvaez, Manuel
AU - Pérez-alea, Mileidys
AU - Agnati, Luigi F.
AU - Ciruela, Francisco
AU - Belluardo, Natale
AU - Fuxe, Kjell
PY - 2011/6/1
Y1 - 2011/6/1
N2 - Fibroblast growth factor receptor 1 (FGFR1) is known to be activated by homodimerization in the pres-ence of both the FGF agonist ligand and heparan sulfate glycosaminoglycan. FGFR1 homodimers in turntrigger a variety of downstream signaling cascades via autophosphorylation of tyrosine residues in thecytoplasmic domain of FGFR1. By means of Bioluminescence Energy Resonance Transfer (BRET) as a signof FGFR1 homodimerization, we evaluated in HEK293T cells the effects of all known FGF agonist ligandson homodimer formation. A significant correlation between BRET2signaling and ERK1/2 phosphorylationwas observed, leading to a further characterization of the binding and signaling properties of the FGF sub-families. FGF agonist ligand-FGFR1 binding interactions appear as the main mechanism for the control ofFGFR1 homodimerization and MAPK signaling which demonstrated a high correlation. The bioinformaticanalysis 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 par-ticipate in the FGFR1 homodimerization interface interaction. The findings also reveal that FGF agonistligands within the same subfamily of the FGF gene family produced similar increases in FGFR1 homodi-mer formation and MAPK signaling. Thus, the evolutionary relationship within this gene family appearsto have a distinct functional relevance.
AB - Fibroblast growth factor receptor 1 (FGFR1) is known to be activated by homodimerization in the pres-ence of both the FGF agonist ligand and heparan sulfate glycosaminoglycan. FGFR1 homodimers in turntrigger a variety of downstream signaling cascades via autophosphorylation of tyrosine residues in thecytoplasmic domain of FGFR1. By means of Bioluminescence Energy Resonance Transfer (BRET) as a signof FGFR1 homodimerization, we evaluated in HEK293T cells the effects of all known FGF agonist ligandson homodimer formation. A significant correlation between BRET2signaling and ERK1/2 phosphorylationwas observed, leading to a further characterization of the binding and signaling properties of the FGF sub-families. FGF agonist ligand-FGFR1 binding interactions appear as the main mechanism for the control ofFGFR1 homodimerization and MAPK signaling which demonstrated a high correlation. The bioinformaticanalysis 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 par-ticipate in the FGFR1 homodimerization interface interaction. The findings also reveal that FGF agonistligands within the same subfamily of the FGF gene family produced similar increases in FGFR1 homodi-mer formation and MAPK signaling. Thus, the evolutionary relationship within this gene family appearsto have a distinct functional relevance.
UR - http://linkinghub.elsevier.com/retrieve/pii/S0006291X11008527
U2 - 10.1016/j.bbrc.2011.05.085
DO - 10.1016/j.bbrc.2011.05.085
M3 - Article
SN - 0006-291X
VL - 409
SP - 764
EP - 768
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -