A Novel Role for IGF-1 Receptor in Growth Hormone Action

IGF-1 受体在生长激素作用中的新作用

• 批准号: 9178068
• 负责人: Stuart J Frank
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178068
• 关键词: Acute; Address; Alpha Cell; Area; Binding; Biological Assay; Bioluminescence; Cancer Biology; Cells; Chimera organism; Collaborations; Complement; Coupled; Coupling; Cytokine Receptors; Data; Dominant-Negative Mutation; Down-Regulation; Elements; Endocrine; Extracellular Domain; Extrahepatic; Functional disorder; Gene Expression; Genes; Growth; Growth Disorders; Growth Hormone Receptor; Hepatic; Hormone Responsive; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Islet Cell; JAK2 gene; Knock-out; Knowledge; Liver; Luciferases; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; Mutagenesis; Osteoblasts; Outcome; Pancreas; Pathway interactions; Phosphotransferases; Physiological; Physiology; Production; Protein Tyrosine Kinase; Proteins; Proteomics; Recombinants; Regulation; Reporting; Role; Signal Transduction; Somatomedins; Somatotropin; Stat5 protein; System; Testing; Therapeutic; Tissues; Work; base; cell type; glucose metabolism; hormone sensitivity; in vivo; member; metabolic phenotype; mutant; novel; novel strategies; novel therapeutics; prostate cancer cell; public health relevance; receptor; receptor binding; reconstitution; response

 DESCRIPTION (provided by applicant): Growth hormone (GH) regulates growth and metabolism by binding GH receptor (GHR), a cytokine receptor superfamily member, in target tissues. This activates the GHR-associated cytoplasmic tyrosine kinase, JAK2, and several signaling systems including STAT5. An important GH-induced outcome in some cell types is STAT5-mediated expression of the insulin-like growth factor (IGF)-1 gene and IGF-1 secretion. For six decades, our appreciation of GH physiology has been influenced by the somatomedin hypothesis, which held that GH-induced hepatically-derived circulating endocrine IGF-1 (aka somatomedin-C) mediates GH's somatogenic actions. Indeed, IGF-1 acts via the type 1 IGF-1 receptor (IGF-1R) to transmit tyrosine-kinase-mediated anabolic signals. However, our novel findings suggest IGF-1R also functions in relevant cell types (preadipocytes, islet -cells, osteoblasts, prostate cancer cells) as a proximal GHR-interacting element to augment GH sensitivity, even absent IGF-1 binding. Specifically, we find GH acutely promotes IGF-1R association with GHR and that IGF-1R deletion reduces acute GH signaling and consequent IGF-1 gene expression. IGF-1R reconstitution in IGF-1R-deleted cells rescues GH responsiveness in a fashion that depends on IGF-1R extracellular domain (ECD) elements. Further, a recombinantly-produced soluble IGF-1R ECD fragment containing these elements binds GHR in response to GH and blunts GH-induced signaling and gene expression in a dominant-negative fashion. Supporting our findings, recent reports indicate overlap in the metabolic phenotypes of mice with islet -cell-specific deletion of either GHR or IGF-1R, suggesting GHR-IGF-1R interaction is physiologically relevant in cell types that coexpress the receptors, unlike liver that is heavily endowed with GHR, but nearly devoid of IGF-1R. We hypothesize: 1) IGF-1R, by virtue of specific interaction with GHR, augments GH-induced somatogenic and metabolic signaling in a physiologically-relevant fashion. 2) Modulation of GHR-IGF-1R interaction could be a therapeutically-relevant target to promote or inhibit GH actions, particularly in non-hepatic tissues that express IGF-1R and when IGF-1R is aberrantly expressed in liver. Specific aims: 1) Define elements in IGF-1R that allow transmembrane-anchored IGF-1R to augment GH signaling; 2) Uncover specific modulators of GH action based on dominant-negative effects of soluble IGF-1R on GH signaling; 3) Examine functional effects of IGF-1R on GHR action in liver and pancreatic -cells in in vivo systems. Proposed studies address a fundamentally novel hypothesis about how GH-induced GHR action is influenced by physical and functional coupling of GHR with IGF-1R and IGF-1R-associated molecules. Our discoveries will enrich the "linear" GHGHRIGF-1IGF-1R pathway (somatomedin hypothesis), suggesting "parallel" GHR/IGF-1R-mediated effects, especially in extrahepatic GH action. Relationships of this work with aspects of metabolic regulation and other areas, including growth disorders and cancer biology, could be many and our results may suggest novel strategies to modulate GH action.

 描述（由适用提供）：生长马（GH）通过结合GH受体（GHR）（一种细胞因子受体超家族成员）在目标时机中调节生长和代谢。这激活了与GHR相关的细胞质酪氨酸激酶，JAK2和包括STAT5在内的几种信号系统。在某些细胞类型中，GH诱导的重要结果是STAT5介导的胰岛素样生长因子（IGF）-1基因和IGF-1分泌的表达。六十年来，我们对GH生理学的欣赏一直受到母系假说的影响，该假说认为GH诱导的肝衍生的循环内分泌IGF-1（aka somatomedIn-c）介导GH GH的体育作用。实际上，IGF-1通过1型IGF-1受体（IGF-1R）起作用，以传递酪氨酸激酶介导的合成代谢信号。然而，我们的新发现表明，IGF-1R在相关细胞类型（前脂肪细胞，胰岛细胞，成骨细胞，前列腺癌细胞）中也起作用，是一种近端的GHR相互作用元件，可增强GH敏感性，甚至没有IGF-1结合。具体而言，我们发现GH急性促进了与GHR的IGF-1R关联，而IGF-1R缺失降低了急性GH信号传导，并导致IGF-1基因表达。 IGF-1R细胞中的IGF-1R重构以取决于IGF-1R细胞外域（ECD）元素的方式挽救GH的反应性。此外，重组生产的固体IGF-1R ECD片段包含这些元素，其响应于GH的GHR和钝的GH诱导的信号传导和基因表达以显性阴性的方式结合。在支持我们的发现时，最近的报告表明，与GHR或IGF-1R的胰岛特异性缺失在小鼠的代谢表型中重叠，这表明GHR-IGF-1R相互作用在与接收器相关的细胞类型中具有物理相关性，与肝脏相同，与GHR相比，与GHR相同，但几乎与GHR赋予了GHR，但几乎是deveoid efoid egfoid geoid ei igf。我们假设：1）IGF-1R，由于与GHR的特定相互作用，以物理上相关的方式增强了GH诱导的种植和代谢信号传导。 2）GHR-IGF-1R相互作用的调节可能是促进或抑制GH作用的治疗性靶标，尤其是在表达IGF-1R的非羊皮组织中以及在肝脏中异常表达IGF-1R时。具体目的：1）定义IGF-1R中允许跨膜锚定的IGF-1R增强GH信号传导的元素； 2）基于固体IGF-1R对GH信号传导的显性阴性作用的特异性调节剂； 3）检查体内系统中IGF-1R对肝脏和胰腺细胞GH作用的功能效应。拟议的研究介绍了一个从根本上新的假设，即GHR与IGF-1R和IGF-1R相关的分子如何影响GH诱导的GHR作用如何影响。我们的发现将丰富“线性”GHGHRGHRGHRIGF-1IGF-1R途径（somatomedIn假设），表明“平行” GHR/IGF-1R介导的效果，尤其是在肝外GH作用中。这项工作与代谢调节和其他领域的各个方面的关系，包括生长障碍和癌症生物学，可能是很多，我们的结果可能表明调节GH作用的新型策略。