FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors
FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors
复制标题
DOI：
10.1128/mcb.20.3.979-989.2000
复制
发表时间：
2000-02-01
影响因子：
5.3
通讯作者：
Lax, I
中科院分区：
文献类型：
--
作者：
Ong, SH;Guy, GR;Lax, I
对接蛋白FRS 2参与细胞外信号从成纤维细胞生长因子（FGF）或神经生长因子（NGF）受体到Ras/促分裂原活化蛋白激酶信号级联的传递。FRS 2家族的两个成员FRS 2 alpha和FRS 2 beta在结构上非常相似。每个由N-末端肉豆蔻化信号、磷酸酪氨酸结合（PTB）结构域和C-末端尾组成，所述C-末端尾含有衔接蛋白Grb 2和蛋白酪氨酸磷酸酶Shp 2的SH 2结构域的多个结合位点。在这里，我们表明，PTB结构域的α和β亚型的FRS 2直接结合到FGF或NGF受体。FRS 2蛋白的PTB结构域与FGFR 1质膜区域中的高度保守序列结合。虽然FGFR 1与FRS 2组成型相互作用，独立于配体刺激和酪氨酸磷酸化，但NGF受体（TrkA）与FRS 2的结合强烈依赖于受体活化。与TrkA的复合物形成依赖于Y 490的磷酸化，Y 490是典型的PTB结构域结合位点，也用作Shc（NPXpY）的结合位点。使用删除和丙氨酸扫描诱变以及肽竞争试验，我们证明，PTB结构域的FRS 2蛋白特异性地识别两种不同的一级结构中的两种不同的受体在磷酸化依赖或独立的方式。此外，在过度表达FGFR 1激酶失活突变体的细胞中，NGF诱导的FRS 2 α酪氨酸磷酸化减少。该实验表明，FGFR 1可以通过隔离两种受体用于传递其信号的共同关键元件来调节经由NGF受体的信号传导。由FRS 2介导的多重相互作用似乎在靶选择和定义几个受体酪氨酸激酶家族的特异性中起重要作用。
The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2 alpha and FRS2 beta, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the 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 receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding 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 in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2 alpha is diminished 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 transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.