MECHANISMS OF SIGNAL TRANSDUCTION THROUGH SURFACE RECEPTORS

白细胞介素5（IL-5）通过与其受体（IL-5 R）相互作用诱导B细胞和嗜酸性粒细胞的增殖和分化，所述受体由两条不同的多肽链α和β（betac）组成。IL-5以高亲和力（Kd，10-150 pM）和低亲和力（Kd，2-10 nM）结合特异性细胞表面受体（IL-5 R）。单独的IL-5 Ra以低亲和力结合IL-5。betac本身不结合IL-5，但与IL-5 R α结合形成高亲和力IL-5 R。α链对IL-5是特异性的，而β链对IL-3和GM-CSF的受体也是共同的。与具有内在激酶结构域的几种生长因子受体家族不同，细胞因子受体与参与受体介导的信号转导的任何已知酶都没有胞质结构域同源性。然而，在各种细胞因子/细胞因子受体系统中已经观察到细胞蛋白的酪氨酸磷酸化，并且认为在它们的信号传导中是至关重要的。最近发现的家族 ...更多信息 非受体酪氨酸激酶Tyk 2、JAK 1和JAK 2与细胞因子受体GM-CSF和IL-3有关。我们已经表明，IL-5诱导在IL-5依赖性早期B细胞系T88-M中迁移到约130至140、92、53、48和45 kDa的蛋白质的明显酪氨酸磷酸化。在该项目中，我们使用IL-5依赖性早期B细胞系，研究了IL-5 R α在参与IL-5信号转导的分子的酪氨酸磷酸化中的作用，Y16和表达完整或突变IL-5 R α以及完整β c的转染子。结果显示，表达完全缺乏胞质结构域的截短的IL-5 R α的转染子与bc一起对IL-5既不显示蛋白酪氨酸磷酸化也不显示增殖。这证实了IL-5 R α在蛋白酪氨酸磷酸化启动细胞生长中的关键作用。IL-5刺激导致betac和含有Src-同源性2（SH 2）和/或SH 3结构域的蛋白质如磷脂酰肌醇-3（PI-3）激酶、Shc、Vav和HS 1的快速酪氨酸磷酸化，表明它们参与IL-5介导的信号转导。IL-5刺激显著增强JAK 2激酶和B细胞特异性布鲁顿酪氨酸激酶（Btk）的活性，并增加JAK 2激酶的酪氨酸磷酸化。这些结果和最近关于生长因子信号传导的数据一起，由酪氨酸激酶如JAK 2和Btk驱动的多种生化途径参与IL-5信号转导。少

Interleukin 5 (IL-5) induces proliferation and differentiation of B cells and eosinophils by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, alpha and beta (betac). IL-5 binds to a specific cell surface receptor (IL-5R) with both high (Kd, 10-150 pM) and low affinity (Kd, 2-10 nM). The IL-5Ralpha alone binds IL-5 with low affinity. The betac does not bind IL-5 by itself, but does form a high affinity IL-5R in combination with IL-5Ralpha. The alpha chain is specific for IL-5 while betac is common to receptors for IL-3 and GM-CSF,as well. Unlike several growth factor receptor families that possess intrinsic kinase domains, the receptors for cytokines have no cytoplasmic domain homology with any known enzymes involved in receptor-mediated signal transduction. However, tyrosine phosphorylation of cellular proteins has been observed in various cytokine/cytokine receptor systems and believed to be crucial in their signaling. A recently discovered fami … More ly of nonreceptor-tyrosine kinases, including Tyk2, JAK1 and JAK2, was suggested to be associated with cytokine receptors including GM-CSF and IL-3. We have shown that IL-5 induces distinct tyrosine phosphorylation of proteins migrating at about 130 to 140,92,53,48 and 45 kDa in the IL-5-dependent early B cell line, T88-M.In this project, we investigated the role of IL-5Ralpha in tyrosine phosphorylation of molecules involved in IL-5 signal transduction, using an IL-5-dependent early B cell line, Y16 and transfectants expressing intact or mutant IL-5Ralpha together with intact betac. The results revealed that the transfectants expressing truncated IL-5Ralpha, which entirely lacks a cytoplasmic domain, together with bc showed neither protein-tyrosine phosphorylation nor proliferation in response to IL-5. This confirms the critical role of IL-5Ralpha in the protein-tyrosine phosphorylation initiates cell growth. IL-5 stimulation results in rapid tyrosine phosphorylation of betac and proteins containing Src-homology 2 (SH2) and/or SH3 domains such as phosphatidyl-inositol-3 (PI-3) kinase, Shc, Vav and HS1, suggesting their involvement in IL-5 mediated signal transduction. IL-5 stimulation significantly enhanced activities of JAK2 kinase and B-cell specific Bruton's tyrosine kinase (Btk) and increased the tyrosine phosphorylation of JAK2 kinase. These results and recent data on signaling of growth factors taken together, multiple biochemical pathways driven by tyrosine kinases such as JAK2 and Btk are involved in IL-5 signal transduction. Less