Signaling by FGFR1

The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br>

纤维母细胞生长因子（FGF）家族的22个成员通过结合并激活由四种受体酪氨酸激酶（RTKs）编码的不同异构体（分别为FGFR1、FGFR2、FGFR3和FGFR4）来介导其细胞反应。这些受体是调控多个发育过程的关键调节因子，在这些过程中，细胞的命运以及向不同组织谱系的分化得到确定。与其它生长因子不同，FGF与肝素或肝素硫酸蛋白聚糖（HSPG）协同作用以激活FGFR，并诱导多效性反应，从而导致这一大型生长因子家族引起的各种细胞反应。FGFR激活的另一种替代来源是与细胞粘附分子的相互作用，通常在神经细胞膜上的相互作用中，这对于神经元的存活和发展至关重要。<br><br>在配体结合后，受体二聚体形成，其内在的酪氨酸激酶被激活，导致受体上多个酪氨酸残基的磷酸化。这些残基随后作为适配器、对接蛋白或信号酶的SH2（src同源-2）或PTB（磷酸酪氨酸结合）结构域的对接位点。信号复合物被组装并募集到活性受体上，导致一系列磷酸化事件的级联反应。<br><br>这进而刺激了调控细胞增殖、细胞分化、细胞迁移、细胞存活和细胞形态的细胞内信号通路，具体取决于细胞类型或成熟阶段。