FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors

The docking protein FRS2 was implicated in the transmission of extracellula r signals from the fibroblast growth factor (FGF) or nerve growth factor (N GF) receptors to the Ras/mitogen-activated protein kinase signaling cascade . The two members of the FRS2 family, FRS2 alpha and FRS2 beta, are structu rally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing m ultiple binding sites for the SH2 domains of the adapter protein Grb2 and t he protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF re ceptors. The PTB domains of the FRS2 proteins bind to a highly conserved se quence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS 2 constitutively, independent of ligand stimulation and tyrosine phosphoryl ation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on recepto r activation. Complex formation with TrkA is dependent on phosphorylation o f Y490, a canonical PTB domain binding site that also functions as a bindin g site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures i n two different receptors in a phosphorylation-dependent or -independent ma nner. In addition, NGF-induced tyrosine phosphorylation of FRS2 alpha is di minished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmit ting their signals. The multiple interactions mediated by FRS2 appear to pl ay an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.