Growth Hormone Regulation of SH2B1

SH2B1 的生长激素调节

• 批准号: 8324747
• 负责人: CHRISTIN CARTER-SU
• 金额: $ 45.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324747
• 关键词: 16p11.2; Actins; Amino Acid Motifs; Apoptosis; Binding; Biochemical; Brain; Brain-Derived Neurotrophic Factor; Cell Line; Cell Nucleus; Cell Proliferation; Cell membrane; Cell physiology; Cells; Cellular biology; Chromosomes; Code; Complex; Cytoplasm; Cytoskeleton; Cytosol; Data; Defect; Development; Diabetes Mellitus; Disease; Exhibits; FOLH1 gene; Figs - dietary; Focal Adhesions; Genes; Genetic; Goals; Growth; Growth Factor; Hematopoietic; Hormones; Human; Hyperphagia; Imaging Techniques; Immune; Immune System Diseases; Immune response; Immunologics; Impairment; Insulin; Insulin Resistance; Investigation; JAK2 gene; Leptin; Letters; Ligands; Location; Malignant Neoplasms; Mammalian Cell; Mediating; Membrane; Metabolism; Microscope; Molecular; Movement; Multiple Sclerosis; Mus; Mutation; Nerve Growth Factors; Nuclear Import; Nuclear Localization Signal; Obesity; Patients; Personal Satisfaction; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Physiology; Play; Proteins; Proteomics; Recruitment Activity; Research; Role; SH2B gene; Scaffolding Protein; Serine; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Somatotropin; Structure; Symptoms; Testing; Tin; Tyrosine; Work; adapter protein; base; biological systems; cell motility; cytokine; field study; hormone regulation; human disease; innovation; insight; macrophage; mental age; migration; mutant; nervous system disorder; prevent; protein transport; public health relevance; receptor; receptor binding; research study; response; severe early onset obesity

DESCRIPTION (provided by applicant): Exciting recent genetic studies implicate the scaffold protein SH2B1 in human disease. Human mutations in SH2B1 are associated with severe early onset obesity with disproportionately severe insulin resistance, impaired brain development, and, in some cases, short stature. This phenotype (strikingly similar to that of SH2B1-/- mice) is consistent with SH2B1 being a signaling molecule for multiple ligands, including growth hormone (GH), leptin, and insulin. SH2B1 is recruited to JAK2 and is a critical component in GH regulation of the actin cytoskeleton, a prerequisite for cellular proliferation, differentiation and migration. However, the mechanism by which SH2B1 facilitates GH-induced changes in the actin cytoskeleton remains largely unknown. The long-term goal is to understand the mechanism by which SH2B1 contributes to the function of GH and other ligands, and to gain insight into unrecognized cellular actions of GH; new functions of SH2B1; and how scaffold proteins such as SH2B1 move highly regulated and dynamic complexes from membrane-bound receptors to multiple, often remote, sites in the cell (e.g., focal adhesions, lamellipodia, cytoplasm, nucleus). The objective of the current proposal is to understand how SH2B1 regulates assembly and movement of "signaling complexes" and whether dysregulation of these functions contributes to defects in cellular function and ultimately human obesity, insulin-resistance, neurologic disorders, and suppressed growth. The central hypothesis is that SH2B1 facilitates the formation and/or movement of SH2B1 "signaling complexes" to specific locations in the cell (e.g., pm, lamellipodia, cytoplasm, nucleus) in response to GH. These functions of SH2B1 enhance GH regulation of the actin cytoskeleton, GH-induced motility, and GH responses in the nucleus. They are critical to normal human physiology, such that their impairment due to mutation contributes to the dramatic phenotype observed in human patients. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Elucidate the mechanism by which SH2B1 reversibly localizes to the plasma membrane, cytosol and nucleus. 2) Determine the role of SH2B1 in regulating GH-induced changes in the actin cytoskeleton, cell motility, and trafficking of proteins between intracellular compartments. 3) Determine the functional consequences of mutations in SH2B1 associated with human disease. Experiments will use a combination of biochemical, immunologic, cell biology, and imaging techniques standard in the lab. State-of-the-art microscopes, photoactivable probes, proteomics, cell lines and both primary macrophages and MEFs from SH2B1-/- mice, will also be used. The concept that the nuclear localization signal of SH2B1 is a dual function motif that mediates both nuclear import and plasma membrane binding that is regulated by phosphorylation of nearby serines is innovative. The proposed research is significant because it will provide insight into the role of SH2B1 in the function of GH and the numerous other ligands (e.g., leptin, insulin, nerve growth factor) that utilize SH2B1 as a signaling protein. PUBLIC HEALTH RELEVANCE: These studies will provide insight into the role of a multifunctional adapter protein SH2B1 in the function of growth hormone and the many other cytokines, hormones and growth factors (e.g. leptin, insulin, nerve growth factor) that use SH2B1 to mediate their effects in cells. Such insight is critical to our understanding on how growth hormone brings about its well known diverse effects in the body, including body growth and metabolism, and other SH2B1 activating ligands contribute to, prevent and/or alleviate symptoms of a variety of diseases including obesity, various cancers, diabetes, multiple sclerosis, and diseases of the immune system.

描述(由申请人提供)：令人兴奋的最新遗传学研究表明，支架蛋白SH2B1与人类疾病有关。人类SH2B1基因突变与严重的早发性肥胖症、不成比例的严重胰岛素抵抗、大脑发育受损，在某些情况下，身材矮小有关。这种表型(与SH2B1-/-小鼠惊人地相似)与SH2B1是包括生长激素(GH)、瘦素和胰岛素在内的多种配体的信号分子是一致的。SH2B1被招募到JAK2中，是GH调节肌动蛋白细胞骨架的关键成分，GH是细胞增殖、分化和迁移的先决条件。然而，SH2B1促进GH诱导的肌动蛋白细胞骨架变化的机制仍然很大程度上是未知的。长期目标是了解SH2B1促进GH和其他配体功能的机制，并深入了解GH未知的细胞作用；SH2B1的新功能；以及支架蛋白(如SH2B1)如何将高度调控的动态复合体从膜结合的受体移动到细胞中多个通常较远的位置(例如，焦点粘连、片状脂膜、细胞质、细胞核)。目前这项提案的目的是了解SH2B1如何调控“信号复合体”的组装和移动，以及这些功能的失调是否会导致细胞功能缺陷，最终导致人类肥胖、胰岛素抵抗、神经紊乱和生长受抑。中心假说是SH2B1促进SH2B1“信号复合体”的形成和/或移动到细胞中特定的位置(如PM、片状脂膜、细胞质、细胞核)，以响应GH。SH2B1的这些功能增强了GH对肌动蛋白细胞骨架的调节、GH诱导的运动和细胞核内的GH反应。它们对正常的人类生理至关重要，因此它们因突变造成的损害导致了在人类患者中观察到的戏剧性表型。在强大的初步数据的指导下，这一假说将通过追求三个具体目标来检验：1)阐明SH2B1可逆定位于质膜、细胞质和细胞核的机制。2)确定SH2B1在调节GH诱导的肌动蛋白细胞骨架、细胞运动和细胞间蛋白质转运中的作用。3)确定SH2B1突变与人类疾病相关的功能后果。实验将使用实验室标准的生化、免疫学、细胞生物学和成像技术的组合。还将使用最先进的显微镜、可光激活的探针、蛋白质组学、细胞系以及来自SH2B1-/-小鼠的原代巨噬细胞和MEF。SH2B1的核定位信号是一个双重功能基序，既介导核输入，又调节质膜结合，受邻近丝氨酸的磷酸化调节，这一概念是创新的。这项拟议的研究具有重要意义，因为它将深入了解SH2B1在生长激素和许多其他利用SH2B1作为信号蛋白的配体(如瘦素、胰岛素、神经生长因子)的功能中所起的作用。 公共卫生相关性：这些研究将深入了解多功能适配蛋白SH2B1在生长激素以及许多其他细胞因子、激素和生长因子(如瘦素、胰岛素、神经生长因子)的功能中所起的作用，这些细胞因子、激素和生长因子使用SH2B1来调节它们在细胞中的作用。这种洞察力对于我们理解生长激素如何在体内带来众所周知的各种影响，包括身体生长和新陈代谢，以及其他SH2B1激活配体如何有助于、预防和/或缓解各种疾病的症状，包括肥胖、各种癌症、糖尿病、多发性硬化症和免疫系统疾病，是至关重要的。