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（由申请人提供）：生长激素 (GH) 通过结合靶组织中的细胞因子受体超家族成员 GH 受体 (GHR) 来调节生长和代谢，这会激活 GHR 相关的细胞质酪氨酸激酶、JAK2 和多种信号系统。包括 STAT5，某些细胞类型中 GH 诱导的一个重要结果是 STAT5 介导的胰岛素样生长因子 (IGF)-1 基因的表达和 IGF-1 的分泌。我们对 GH 生理学的认识受到生长调节素假说的影响，该假说认为 GH 诱导的肝源性循环内分泌 IGF-1（又名生长调节素-C）介导 GH 的生长作用。事实上，IGF-1 通过 1 型 IGF- 发挥作用。 1 受体 (IGF-1R) 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 也在相关细胞类型中发挥作用。 （前脂肪细胞、胰岛  细胞、成骨细胞、前列腺癌细胞）作为近端 GHR 相互作用元件，即使在没有 IGF-1 结合的情况下，也能增强 GH 敏感性。具体来说，我们发现 GH 会急剧促进 IGF-1R 与 GHR 的关联，并且 IGF- 1R 缺失减少了急性 GH 信号传导，随后 IGF-1R 缺失细胞中 IGF-1R 的重建可挽救 GH。此外，重组产生的可溶性 IGF-1R ECD 片段含有这些元件，可响应 GH 结合 GHR，并减弱 GH 诱导的信号传导和基因表达。最近的报告表明，胰岛 β 细胞特异性删除 GHR 或 IGF-1R 的小鼠的代谢表型存在重叠，这支持了我们的发现。 GHR-IGF-1R 相互作用在共表达受体的细胞类型中具有生理相关性，这与富含 GHR 但几乎缺乏 IGF-1R 的肝脏不同。我们进化出了：1) IGF-1R，凭借与 GHR 的特异性相互作用。 ，以生理相关的方式增强 GH 诱导的体生成和代谢信号传导 2) GHR-IGF-1R 相互作用的调节可能是促进或抑制的治疗相关靶点。 GH 作用，特别是在表达 IGF-1R 的非肝组织中以及当 IGF-1R 在肝脏中异常表达时。 具体目标： 1) 定义 IGF-1R 中允许跨膜锚定的 IGF-1R 增强 GH 信号传导的元件； ) 基于可溶性 IGF-1R 对 GH 信号传导的显性负效应，发现 GH 作用的特定调节剂 3) 检查 IGF-1R 对 GH 信号传导的功能影响；体内系统中肝脏和胰腺  细胞中 GHR 的作用提出了一个全新的假设，即 GH 诱导的 GHR 作用如何受到 GHR 与 IGF-1R 和 IGF-1R 相关分子的物理和功能耦合的影响。这些发现将丰富“线性”GHGHRIGF-1IGF-1R途径（生长调节素假说），暗示“平行” GHR/IGF-1R 介导的作用，特别是在肝外 GH 作用中，与代谢调节和其他领域（包括生长障碍和癌症生物学）的关系可能有很多，我们的结果可能会提出调节 GH 作用的新策略。