FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

• DOI: 10.1128/mcb.20.3.979-989.2000
• Publication Date: 2002-07-27T09:58:18Z
• Authors: S. H. Ong; G. R. Guy; Y. R. Hadari; S. Laks; N. Gotoh; J. Schlessinger; I. Lax
• Keywords: GRB2

AbstractThe docking protein FRS2 was implicated in the transmission of extracellular signals from fibroblast growth factor (FGF) or nerve (NGF) receptors to Ras/mitogen-activated kinase signaling cascade. The two members family, FRS2α and FRS2β, are structurally very similar. Each is composed an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, C-terminal tail containing multiple binding sites for SH2 domains adapter Grb2 tyrosine phosphatase Shp2. Here we show that PTB both α β isoforms bind directly FGF NGF receptors. proteins highly conserved sequence juxtamembrane region FGFR1. While FGFR1 interacts with constitutively, independent ligand stimulation phosphorylation, receptor (TrkA) strongly dependent on activation. Complex formation TrkA phosphorylation Y490, canonical domain site also functions as Shc (NPXpY). Using deletion alanine scanning mutagenesis well peptide competition assays, demonstrate specifically recognize different primary structures phosphorylation-dependent -independent manner. In addition, NGF-induced diminished cells overexpress kinase-inactive mutant This experiment suggests may regulate via by sequestering common key element which utilize transmitting their signals. interactions mediated appear play important role target selection defining specificity several families kinases. ACKNOWLEDGMENTThis work supported fellowship grant HFSPO.