IL-4-INDUCED SIGNAL TRANSDUCTION PATHWAYS IN HEMATOPOIETIC CELLS

IL-4 诱导的造血细胞信号转导途径

• 批准号: 3752757
• 负责人: J H PIERCE
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752757
• 关键词: biological signal transduction; cell cycle; enzyme substrate; growth factor receptors; hematopoietic stem cells; human tissue; insulin; interleukin 4; mitogens; phosphoproteins; phosphorylation; point mutation; protein tyrosine kinase; tissue /cell culture; tyrosine

Signal transduction mediated by IL-4 in hematopoietic cell lines was shown to induce tyrosine phosphorylation of cellular proteins. The most prominent IL-4-induced phosphorylated substrate was a 170 kd protein. designated 4PS (IL-4-induced phosphotyrosine substrate). the dose required to observe tyrosine phosphorylation of 4PS correlated with mitogenicity induced by IL-4. It was shown that IL-4. insulin and IGF-1 share the overlapping signaling pathways in hematopoietic cells by utilizing 4PS. Moreover. 4PS was shown to be related but not identical to IRS-I. the principal substrate of insulin and IGF-1 in cells of connective tissue origin. 32D cells. a factor-dependent murine myeloid cell line. did not proliferate in response to the IL-4 or insulin. even when either receptor was overexpressed. Examination of tyrosine phosphorylation pattern induced by IL-4 or insulin revealed that there was no detectable 4PS expressed in 32D cells. When an IRS-I CDNA was introduced into either parental or receptor overexpressed 32D cells. the mitogenic sensitivity to IL-4 or insulin was reconstituted. These results indicate that growth factors that bind to unrelated receptors can utilize similar signaling elements in hematopoietic cells. and that IRS-I and 4PS are functionally similar proteins that are essential for insulin- and IL-4-induced proliferation. Functional domains of IL-4 receptor importance for signal transduction were studied by introducing a series of human IL-4 receptor mutants into IRS-I-expressing 32D cells. Results suggested that an acidic region within the cytoplasmic domain between amino acids 437 and 557 was critical for IL-4 signaling. This region contains a sequence motif 488- PLXXXXNPXYXSXSD-502. also found in the intracellular domain of insulin and IGF-I receptors. and was designated I4R motif. Point mutation on tyrosine 497 within this I4R motif greatly reduced IRS-I phosphorylation and cell proliferation in response to human IL-4. These results suggest that the central tyrosine within I4R motif is important for IL-4 signaling.

IL-4介导的造血细胞信号转导 被证明能诱导细胞蛋白质的酪氨酸磷酸化。最多的 IL-4诱导的磷酸化底物是一个170kd的蛋白质。 命名为4PS(IL-4诱导的磷酸酪氨酸底物)。剂量 需要观察4PS的酪氨酸磷酸化与 IL-4诱导的有丝分裂原。结果表明，IL-4与IL-4呈正相关。胰岛素与胰岛素样生长因子-1 通过以下途径共享造血细胞中重叠的信号通路 利用4PS。更有甚者。4P被证明是相关的，但不完全相同 至IRS-I。胰岛素和胰岛素样生长因子-1在人卵巢癌细胞中的主要底物 结缔组织起源。 32D细胞。一种依赖因子的小鼠髓系细胞系。vbl.没有，没有 在IL-4或胰岛素刺激下增殖。即使当任一受体 被过度表达了。酪氨酸磷酸化模式的检测 经IL-4或胰岛素诱导后，未检测到4PS 在32D细胞中表达。当IRS-I CDNA被引入到任何一个 亲本或受体高表达32D细胞。有丝分裂的敏感性 重组IL-4或胰岛素。这些结果表明，增长 与无关受体结合的因子可以利用类似的信号 造血细胞中的元素。IRS-I和4PS在功能上 胰岛素和IL-4诱导的相似蛋白质 扩散。 IL-4受体在信号转导中的重要功能域 通过将一系列人IL-4受体突变体引入到 表达IRS-I的32D细胞。结果表明，一个酸性区域 在氨基酸437和557之间的细胞质区域是 对IL-4信号转导至关重要。该区域包含一个序列基序488- PLXXXXNPXYXSXSD-502。在胰岛素的胞内结构域中也有发现 和IGF-I受体。并被指定为I4R基序。点突变打开 I4R基序中的酪氨酸497极大地降低了IRS-I的磷酸化 和细胞对人IL-4的反应。这些结果表明 I4R基序中的中心酪氨酸对IL-4很重要 发信号。