GROWTH HORMONE RECEPTOR SIGNALING

生长激素受体信号传导

• 批准号: 2734179
• 负责人: CORINNE M SILVA
• 金额: $ 11.26万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-11 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2734179
• 关键词: 3T3 cells; DNA binding protein; biological signal transduction; cell cycle proteins; clone cells; cytokine receptors; dimer; enzyme activity; enzyme substrate; gel mobility shift assay; guanine nucleotide binding protein; hormone receptor; immunoprecipitation; interferon alpha; interferon gamma; molecular cloning; phosphoproteins; phosphorylation; protein purification; protein sequence; protein tyrosine kinase; protein tyrosine phosphatase; somatotropin; transcription factor; western blottings

Although the integral role that growth hormone (GH) plays in metabolism and the overall growth of an organism is well established, the specific and varied effects of GH on different cells, tissues and organs are only now becoming recognized and studied. Most notably, the effects of GH on immune system function are still not well appreciated. Analysis of the effects of GH on the immune system will be vital in order to understand its role in normal immunological function, and more significantly to evaluate its potential utility in treating immunologic disease. Understanding the actions of GH on any cell requires characterizing the molecular mechanisms by which the membrane bound receptor for GH is activated and transmits its signal intracellularly. Studying GH receptor signalling in the immune system has a key advantage that serves as the basis for much of this application; namely it should be possible to make mechanistic comparisons between signalling by the GH receptor and signalling by receptors for other cytokines with well-defined roles in immune cell function. The GH receptor has structural similarities to the receptors for cytokines such as the interleukins (ILs) and colony stimulating factors (CSFs) as well as the interferons (IFNs alpha and gamma). In addition, these receptors have a common mechanism of intracellular signalling which involves tyrosine phosphorylation of putatively similar molecules. This provides a framework in which to study the mechanisms of GH receptor activation and signalling. Although the members of this family share common components in their intracellular pathway of signal transduction, they have obvious distinct biological actions which presumably arise from specific differences in these signalling pathways. The IM-9 cell, a human myeloma derived B-lymphocyte line, provides a unique opportunity to unravel the mechanisms underlying this specificity of response in a cell of the immune system. By identifying those signalling steps that are similar as well as elucidating those which are unique will provide insight into the role of GH in immune cell function. The potential mechanisms which confer specificity to the intracellular signalling pathways of the GH and IFNgamma receptors will be analyzed by pursuit of the following Specific Aims: (I) Identification of the tyrosine kinase(s) responsible for the GH activated tyrosine phosphorylations in IM-9 cells and characterization of their specificity regarding activation by the GH receptor. (II) Characterization of the 93 kDa protein which is tyrosine phosphorylated in response to GH and determination of its relationship to the 91 kDa protein which is tyrosine phosphorylated in response to IFNgamma. (III) Determination of the role of tyrosine phosphatase(s) in signalling by the GH receptor in IM-9 cells. (IV) Characterization of the signalling path way of GH activation of MAP kinase in 3T3-F442A cells as an approach to understanding how this signalling path way is different in IM-9 cells.

尽管生长激素 (GH) 在新陈代谢中发挥着不可或缺的作用 并且有机体的整体生长已确定，具体 GH对不同细胞、组织和器官的不同作用只是 现在正逐渐被认识和研究。最值得注意的是，GH 对 免疫系统的功能尚未得到充分认识。分析 为了理解 GH 对免疫系统的影响至关重要 它对正常免疫功能的作用，更重要的是 评估其在治疗免疫疾病中的潜在效用。 了解 GH 对任何细胞的作用需要表征 GH 膜结合受体的分子机制 激活并在细胞内传输其信号。研究 GH 受体 免疫系统中的信号传导有一个关键优势，即 本应用程序大部分内容的基础；即应该可以使 GH 受体信号传导之间的机制比较 其他细胞因子受体的信号传导在细胞因子中具有明确的作用 免疫细胞功能。 GH 受体与 GH 受体具有结构相似性 细胞因子受体，例如白细胞介素 (IL) 和集落 刺激因子 (CSF) 以及干扰素 (IFNs α 和 IFNs) 伽玛）。此外，这些受体有一个共同的机制： 细胞内信号传导涉及酪氨酸磷酸化 假定相似的分子。 这提供了一个学习框架 GH 受体激活和信号传导机制。虽然 该家族的成员在细胞内具有共同的成分 信号转导途径，具有明显不同的生物学特性 可能由这些具体差异引起的行动 信号通路。 IM-9 细胞，一种人骨髓瘤来源的 B 淋巴细胞 线，提供了一个独特的机会来揭示潜在的机制 免疫系统细胞中这种反应的特异性。 经过 识别那些相似的信号步骤并阐明 那些独特的将深入了解 GH 在免疫中的作用 细胞功能。赋予特异性的潜在机制 GH 和 IFNγ 受体的细胞内信号传导途径 通过追求以下具体目标进行分析： (I) 确定 负责 GH 激活酪氨酸的酪氨酸激酶 IM-9 细胞中的磷酸化及其特异性的表征 关于 GH 受体的激活。 （二）93的特征 kDa 蛋白，响应 GH 而被酪氨酸磷酸化， 确定其与 91 kDa 蛋白质酪氨酸的关系 响应 IFNγ 磷酸化。 （三）角色的确定 IM-9 细胞中 GH 受体信号传导中的酪氨酸磷酸酶。 (四) GH激活MAP信号通路方式表征 3T3-F442A 细胞中的激酶作为了解其如何发挥作用的方法 IM-9细胞中的信号传导途径不同。

项目成果

GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts.

正常和拉伦综合征成纤维细胞中的 GH 和表皮生长因子信号传导。

• DOI: 10.1210/endo.143.7.8909
• 发表时间: 2002
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Silva,CorinneM;Kloth,MichaelT;Whatmore,AndrewJ;Freeth,JamesS;Anderson,Neil;Laughlin,KristenK;Huynh,Trang;Woodall,AlysonJ;Clayton,PeterE
• 通讯作者: Clayton,PeterE

Growth hormone stimulation of the mitogen-activated protein kinase pathway is cell type specific.

生长激素对丝裂原激活蛋白激酶途径的刺激具有细胞类型特异性。

• DOI: 10.1210/endo.139.4.5884
• 发表时间: 1998
• 期刊: Endocrinology.
• 作者: Love,DW;Whatmore,AJ;Clayton,PE;Silva,CM
• 通讯作者: Silva,CM