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Growth Hormone Receptors and Actions

生长激素受体和作用

基本信息

批准号：
7992537
负责人：
CHRISTIN CARTER-SU
金额：
$ 6.65万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-28 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992537
关键词：
Adult Affect Basic Science Binding Binding Sites Child Chronic Kidney Failure Cities Cloning Complex Cytokine Receptors Cytoskeleton Denmark Disease Docking Expression Library Face Family Foundations Fox Chase Cancer Center Funding Gene Expression Genes Grant Growth Growth Hormone Receptor Growth Hormone Signaling Pathway Human Resources Hybrids Institutes Instruction Insulin Receptor Internet JAK2 gene Janus kinase Knowledge Life Ligand Binding Maps Mass Spectrum Analysis Metabolic Pathway Metabolism Michigan Microarray Analysis Minnesota Molecular Mutate Names Pathway interactions Pharmaceutical Preparations Phospho-Specific Antibodies Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Physiological Play Population Principal Investigator Printing Protein Binding Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Receptor Signaling Recruitment Activity Regulation Research Research Design Research Project Grants Role SH2B gene SHPS-1 protein STAT protein Scientist Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Site Somatotropin System Testing Therapeutic Agents Tissues Turner&apos s Syndrome Tyrosine Tyrosine Phosphorylation United States National Institutes of Health Universities Yeasts anti aging cytokine design growth hormone deficiency hormone regulation human GHR protein insight medical schools member mutant new growth programs receptor research study response src Homology Region 2 Domain two-dimensional

项目摘要

One of the most exciting advances in understanding the molecular actions of growth hormone (GH) was the identification of the tyrosine (Tyr) kinase JAK2 as a receptor-associated signaling molecule for the GH receptor (GHR). In this competing renewal we shall continue to test the hypothesis that activation of JAK2 in response to GH is a required initial step in GH signal transduction that results in the phosphorylation of multiple Tyr in GHR and JAK2. These phosphorylated Tyr serve as binding sites for molecules in various GH signaling pathways. During the past funding period, multiple signaling proteins and signaling pathways for GH were identified and/or characterized. Some of these signaling proteins were found to be activated as a consequence of binding to JAK2 (SH2-B, SIRPa) and others as a consequence of binding to GHR (SHP-2, StatS). The docking site for others remains ambiguous (She, IRS, Stats 1 and 3). Efforts were initiated to identify the Tyr within GHR and JAK2 that are phosphorylated by JAK2, with 3 phosphorylated Tyr within JAK.2 being identified. In Aims land 2 of the current proposal, Tyr within JAK2 and GHR that are phosphorylated in response to GH will be identified and their regulation studied using a combination of 2 dimensional phosphopeptide mapping, phosphospecific antibodies and mass spectrometry. Aim 3 will use microarray technology to identify populations of genes that are regulated by GH and determine whether expression of specific subpopulations of these genes require specific phosphorylated tyrosines in GHR and JAK2. Aim 4 will determine which phosphorylated Tyr within GHR and JAK2 bind to known GH signaling proteins. Finally, Aim 5 will use yeast 2-hybrid system to identify new signaling proteins that bind preferentially to activated, tyrosyl phosphorylated JAK2 and characterize their regulation by GH. To identify proteins that bind to specific phosphorylated tyrosines within GHR and JAK2, A expression libraries will be screened with phosphopeptides corresponding to phosphorylated Tyr containing sequences within GHR and JAK2. These studies will provide needed insight into: 1) the initiating steps in GHR signal transduction; 2) new signaling proteins and genes that are regulated by GH; 3) new signaling pathways utilized by GH; 4) the mechanisms by which these pathways are initiated; and 5) pathways that interact, either because they compete for the same binding site in GHR and/or JAK2, lie downstream of a common initial signaling molecule or require input form multiple upstream pathways. This insight should be of great assistance in delineating the molecular mechanisms by which GH elicits its diverse effects on growth and metabolism as well as in deciphering similarities and differences in the signaling pathways utilized by the cytokines that activate JAK kinases. Ultimately, it should facilitate the design the therapeutic agents that target specific growth and metabolic pathways regulated by GH and/or these other cytokines.

在了解生长激素（GH）的分子作用方面最令人兴奋的进展之一是鉴定出酪氨酸（Tyr）激酶JAK 2作为GH受体（GHR）的受体相关信号分子。在这一竞争性更新中，我们将继续检验以下假设：响应于GH的JAK 2活化是GH信号转导中所需的初始步骤，其导致GHR和JAK 2中多个Tyr的磷酸化。这些磷酸化的Tyr作为各种GH信号通路中分子的结合位点。在过去的资助期间，GH的多种信号蛋白和信号通路被鉴定和/或表征。发现这些信号蛋白中的一些作为与JAK 2结合的结果而被激活。（SH 2-B，SIRPa）和其他作为与GHR结合的结果（SHP-2，StatS）。其他人的对接地点仍然模糊不清（她，国税局，统计1和3）。开始努力鉴定GHR和JAK 2内被JAK 2磷酸化的Tyr，其中鉴定了JAK 2内的3个磷酸化Tyr。在当前提案的目的和2中，将鉴定JAK 2和GHR中响应GH而磷酸化的Tyr，并使用二维磷酸肽图谱、磷酸特异性抗体和质谱法的组合研究其调节。目标3将使用微阵列技术来鉴定受GH调控的基因群体，并确定这些基因的特定亚群的表达是否需要GHR和JAK 2中的特定磷酸化酪氨酸。目的4将确定GHR和JAK 2中哪些磷酸化Tyr与已知GH信号蛋白结合。最后，Aim 5将使用酵母双杂交系统来鉴定新的信号蛋白，优先活化，酪氨酰磷酸化JAK 2和表征其调节GH。为了鉴定与GHR和JAK 2内的特异性磷酸化酪氨酸结合的蛋白质，将用对应于GHR和JAK 2内含有磷酸化Tyr的序列的磷酸肽筛选A表达文库。这些研究将为以下方面提供所需的见解：1）GHR信号转导的启动步骤; 2）受GH调节的新信号蛋白和基因; 3）GH利用的新信号通路; 4）GH的作用机制这些途径被启动;和5）相互作用的途径，或者因为它们竞争GHR和/或JAK 2中的相同结合位点，位于共同的初始信号分子的下游，或者需要来自多个上游途径的输入。这种见解应该是很大的帮助，在描绘的分子机制，GH elevites其对生长和代谢的不同影响，以及在破译的相似性和差异，激活JAK激酶的细胞因子所利用的信号通路。最终，它应该有助于设计靶向由GH和/或这些其他细胞因子调节的特定生长和代谢途径的治疗剂。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Demonstration of growth hormone (GH) receptor-associated tyrosine kinase activity in multiple GH-responsive cell types.

展示多种 GH 反应性细胞类型中生长激素 (GH) 受体相关的酪氨酸激酶活性。

DOI：
10.1210/endo-127-5-2506
发表时间：
1990
期刊：
Endocrinology
影响因子：
4.8
作者：
Stred,SE;Stubbart,JR;Argetsinger,LS;Shafer,JA;Carter-Su,C
通讯作者：
Carter-Su,C

Antibodies to cytoplasmic sequences of cloned liver growth hormone (GH) receptors recognize GH receptors associated with tyrosine kinase activity.

针对克隆肝生长激素 (GH) 受体细胞质序列的抗体可识别与酪氨酸激酶活性相关的 GH 受体。

DOI：
10.1210/endo-129-3-1659
发表时间：
1991
期刊：
Endocrinology
影响因子：
4.8
作者：
Stubbart,JR;Barton,DF;Tai,PK;Stred,SE;Gorin,E;Goodman,HM;Carter-Su,C
通讯作者：
Carter-Su,C

Growth hormone-promoted tyrosyl phosphorylation of a 121-kDa growth hormone receptor-associated protein.

生长激素促进 121 kDa 生长激素受体相关蛋白的酪氨酰磷酸化。

DOI：
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Wang,X;Möller,C;Norstedt,G;Carter-Su,C
通讯作者：
Carter-Su,C

Enu mutagenesis identifies a novel platelet phenotype in a loss-of-function Jak2 allele.

Enu 诱变在功能丧失的 Jak2 等位基因中鉴定出一种新的血小板表型。

DOI：
10.1371/journal.pone.0075472
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Anderson,NicoleM;Javadi,Mojib;Berndl,Elizabeth;Berberovic,Zorana;Bailey,MonicaL;Huang,Kai;Flenniken,AnnM;Osborne,LucyR;Adamson,SLee;Rossant,Janet;Carter-Su,Christin;Wang,Chen;McNagny,KellyM;Paulson,RobertF;Minden,MarkD
通讯作者：
Minden,MarkD

Differential regulation of two glucose transporters by chronic growth hormone treatment of cultured 3T3-F442A adipose cells.

培养的 3T3-F442A 脂肪细胞的慢性生长激素处理对两种葡萄糖转运蛋白的差异调节。