REGULATION OF EPO RECEPTOR SIGNALING BY SH-PTP1

SH-PTP1 对 EPO 受体信号传导的调节

• 批准号: 2882788
• 负责人: BENJAMIN G. NEEL
• 金额: $ 27.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-15 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882788
• 关键词: JAK kinase; binding proteins; biological signal transduction; cell cycle; chemical association; enzyme activity; enzyme structure; erythroid stem cell; erythroleukemia; erythropoietin; gene expression; genetically modified animals; growth factor receptors; hematopoietic stem cells; immunoprecipitation; laboratory mouse; mutant; phenylalanine; phosphorylation; point mutation; posttranslational modifications; protein tyrosine phosphatase; receptor binding; receptor expression; western blottings; yeasts

DESCRIPTION: (Adapted from investigator's abstract) Protein phosphorylation on tyrosine residues plays an important role in the regulation of many physiologic processes. The dephosphorylation of these proteins is regulated by a group of protein tyrosyl phosphatases (PTPs) which have generally not been well studied. In hematopoiesis, homeostasis is maintained by the actions of growth factors and cytokines, most of which signal through protein kinases or receptor associated protein kinases. The erythropoietin receptor associates with the JAK2 tyrosine kinase upon binding of erythropoietin. Abnormalities in PTK pathways can result in hematopoietic failure or in diseases of hyperproliferation such as erythrocytosis or erythroleukemia. The overall goal of this application is to define how the SH2 containing non- transmembrane tyrosine phosphatase, SHPTP1, controls EPO receptor signal transduction and how binding of the EPO receptor to SHPTP1 controls SHPTP1 activity. The applicant proposes to define the mechanism of regulation of JAK2 by SHPTP1 in molecular detail. The exact tyrosine residue to which SHPTP1 binds in the EPO receptor will be defined. The applicant will also determine whether a familial erythrocytosis syndrome is due to abrogation of the EPO receptor/SHPTP1 interaction. He will ask if sustained JAK2 expression is sufficient to confer EPO hypersensitivity and whether the inactivation of JAK2 by SHPTP1 requires other interacting proteins. The biochemical basis for differences in specificity between SHPTP1 and its close relative, SHPTP2, in EPO receptor signalling will be determined. He will also determine whether SHPTP1 regulates signalling molecules other than JAK2 and pathways other than proliferation. The in vivo significance of the SHPTP1 EPO receptor interaction will be determined by creating transgenic mice that express EPO receptors unable to bind SHPTP1. Finally, the precise sequence determinants for phosphotyrosyl peptide binding to the amino terminal SH2 domain of SHPTP1 will be defined and the mechanism by which the SH2 domains of SHPTP1 basally repressed PTP activity will be elucidated. The results of the proposed studies may yield new insights into how PTPs contribute to the control of normal hematopoiesis and its disruption in human disease.

描述：（改编自研究者的摘要）蛋白质 酪氨酸残基的磷酸化在 许多生理过程的调节。这些物质的去磷酸化 蛋白质由一组蛋白质酪氨酰磷酸酶 (PTP) 调节 通常没有得到很好的研究。在造血、体内平衡中 大部分是通过生长因子和细胞因子的作用来维持的 通过蛋白激酶或受体相关蛋白发出信号 激酶。促红细胞生成素受体与 JAK2 酪氨酸相关 与促红细胞生成素结合后的激酶。 PTK 通路异常可以 导致造血衰竭或过度增殖疾病 例如红细胞增多症或红白血病。本次活动的总体目标 应用是定义SH2如何含有非跨膜 酪氨酸磷酸酶 SHPTP1 控制 EPO 受体信号转导 以及 EPO 受体与 SHPTP1 的结合如何控制 SHPTP1 活性。 申请人建议通过以下方式定义JAK2的调节机制： SHPTP1 分子细节。 SHPTP1 的确切酪氨酸残基 将定义与 EPO 受体的结合。申请人还将 确定家族性红细胞增多症是否是由于废除引起的 EPO 受体/SHPTP1 相互作用的研究。他会询问JAK2是否持续 表达足以赋予 EPO 超敏性，并且是否 SHPTP1 使 JAK2 失活需要其他相互作用的蛋白质。这 SHPTP1 及其特异性差异的生化基础 近亲SHPTP2在EPO受体信号传导中的作用将被确定。 他还将确定SHPTP1是否调节信号分子 JAK2 以外的途径和增殖以外的途径。体内 SHPTP1 EPO 受体相互作用的重要性将被确定 通过创建表达 EPO 受体但无法结合的转基因小鼠 SHPTP1。最后，磷酸酪氨酰的精确序列决定因素 与 SHPTP1 氨基末端 SH2 结构域结合的肽将是 SHPTP1 的 SH2 结构域的定义和机制 受抑制的 PTP 活性将得到阐明。拟议的结果 研究可能会对 PTP 如何促进控制产生新的见解 正常造血作用及其对人类疾病的破坏。