Fibroblast growth factor 1 (FGF-1) induces neurite outgrowth in PC12 cells. parts of FGFR-1 had been defined as conferring sturdy and moderate capabilities respectively for induction of neurite outgrowth to FGFR-3. Analysis of FGF-stimulated activation of transmission transduction revealed the JM region GSK1292263 of FGFR-1 conferred strong and sustained tyrosine phosphorylation of several cellular proteins and activation of MAP kinase. The SNT/FRS2 protein was demonstrated to be one of the cellular substrates preferentially phosphorylated by chimeras containing the JM domain of FGFR-1. SNT/FRS2 links FGF signaling to the MAP kinase pathway. Thus the ability of FGFR-1 JM domain chimeras to induce strong sustained phosphorylation of this protein would explain the ability of these chimeras to activate MAP kinase and hence neurite outgrowth. The role of the COOH region of FGFR-1 in induction of neurite outgrowth involved the tyrosine residue at amino acid position 764 a site required for phospholipase C gamma binding and activation whereas the JM region functioned primarily through a non-phosphotyrosine-dependent mechanism. In contrast assessment of the chimeras in the pre-B lymphoid cell line BaF3 for FGF-1-induced mitogenesis revealed that the JM region did not play a role in this cell type. These data indicate that FGFR signaling can be regulated at the level of intracellular interactions and that signaling GSK1292263 pathways for GSK1292263 neurite outgrowth and mitogenesis use different regions of the FGFR. The fibroblast growth factor (FGF) family currently comprises 14 members FGF-1 through -14 (6). These growth factors play roles in development angiogenesis wound healing and tumorigenesis (for reviews see references 1 and 20). FGF actions are mediated by the binding and activation of FGF receptor (FGFR) tyrosine kinases. FGFRs are a gene family of four members termed FGFR-1 to -4. These receptors are widely expressed in many tissues and different cell types and the temporal expression of the receptors and ligands is regulated during development (reviewed in reference Rabbit Polyclonal to PITX1. 17). Signals by FGFRs appear to control differentiation as well as proliferation. GSK1292263 Mutations in these receptors have indicated that they may control the differentiation of specific cell types during development. Point mutations of the genes encoding human FGFR-1 -2 or -3 cause different syndromes that involve bone development (reviewed in references 24 and 47) and some of these syndromes (Apert syndrome and thanatophoric dysplasia) may also manifest effects in the central nervous system. In particular point mutations that activate FGFR-3 (25 46 cause dwarfism such as achondroplasia (34 36 hypochondroplasia (2 32 or thanatophoric dysplasia (39 40 Studies analyzing the consequences of null mutations in FGFRs in mice also implicated these receptors as playing a role in development. The knockouts of FGFR-1 or FGFR-2 (9 48 in mice result in embryonic lethality whereas the knockout of FGFR-3 in mice was nonlethal. The FGFR-3-deficient mice developed an overgrowth of the long bones and an abnormal curvature of the spine and tail (5 8 and were deaf (5). The FGFRs are very similar in structure. In particular their tyrosine kinase domains are GSK1292263 highly conserved and they can be activated by overlapping subsets of ligands (17 29 Presently it is not clear how the specificity of signal transduction is achieved. Regulation can take place at two different levels. For example the temporal control of the expression of both ligands and receptors undoubtedly is an important mechanism for regulating signal transduction during development. However in addition the receptors seem to have differing signaling capabilities. Studies have indicated that FGFR-1 is much better at producing mitogenic signals than FGFR-3 and FGFR-4 when assayed in BaF3 cells (3 29 44 In addition we have demonstrated previously that there is a difference between FGFR-1 and -3 in their abilities to induce neurite outgrowth in PC12 cells when activated by FGF-1 (19). FGFR-3 may barely induce neurite outgrowth whereas activation of FGFR-1 induces robust and quick neurite.