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Regulation of somatostatin receptor signaling by receptor interacting proteins.

通过受体相互作用蛋白调节生长抑素受体信号传导。

基本信息

批准号：
9269652
负责人：
AGNES SCHONBRUNN
金额：
$ 8.62万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269652
关键词：
Binding Binding Proteins Brain Bypass Cell Proliferation Cell model Cell secretion Cell surface Cells Clinical Complex Cytoplasmic Tail DLG4 gene Data Defect Drug Targeting Family G-Protein-Coupled Receptors Growth Health Hormonal Hormones Human Individual Islet Cell Tumor Life Ligands Mass Spectrum Analysis Mediating Medical Messenger RNA Molecular Morbidity - disease rate Mutation Names Neurodevelopmental Disorder Neuroendocrine Tumors Neurons Octreotide PDZ protein Pancreas Patients Phosphorylation Physiological Pituitary Gland Pituitary Hormones Pituitary Neoplasms Play Progression-Free Survivals Protein Binding Domain Protein Dephosphorylation Proteins RIPK1 gene Receptor Signaling Regulation Research Resistance Role Scaffolding Protein Signal Pathway Signal Transduction Signal Transduction Pathway Somatostatin Somatostatin Analog Therapy Somatostatin Receptor Somatotropin Symptoms Tertiary Protein Structure Testing Tight Junctions Translations base clinically relevant effective therapy improved insight mRNA Expression mortality neoplastic cell neuropsychiatric disorder neurotransmission novel novel strategies prevent receptor receptor expression receptor function response scaffold somatostatin analog therapeutic target trafficking tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The cell surface expression, intracellular trafficking, and signal transduction by the family of G protein coupled receptors is tightly regulated by numerous proteins that interact with receptor cytoplasmic domains. Mutations in or altered expression of these receptor interacting proteins (RIPs) disrupt the complexes that anchor the receptor and its effectors and thus perturb receptor localization, trafficking and stability and cause defective receptor signaling. Several RIPs have been shown to bind to the sst2A somatostatin (SS) receptor, the therapeutic target for the SS analogs used as primary medical therapy for pituitary and other hormone secreting neuroendocrine tumors. SS analogs slow tumor progression and inhibit the secretion of bioactive tumor products thereby controlling the debilitating and potentially life-threatening symptoms produced by hormone secreting tumors. Unfortunately, SS analogs fail to control hormone hyper-secretion in a large fraction of patients. The factors that cause variability in patient responsiveness to SS analog therapy are not understood but do not result from mutations in the sst2A receptor and cannot be explained by an absence of sst2A mRNA expression. The fundamental hypothesis for this application is that sst2A receptor interacting proteins play a critical role in the responsiveness of hormone secreting tumors to SS analogs and that the interaction of these proteins with the sst2A receptor is dynamically regulated. In this proposal we plan to identify proteins associated with the sst2A receptor in pituitary tumor cells and characterize the functional consequences of the identified interactions on the cell surface expression of the sst2A receptor, on its intracellular trafficking and stability, and on its ability to activate the signal transduction pathways known to mediate SS inhibition of pituitary hormone secretion. In addition, we will determine how the association between the sst2A receptor and its interacting partners is dynamically regulated both at the cell surface and within endocytic compartments. The proposed studies will provide new understanding into the molecular mechanisms that control sst2A receptor signaling, trafficking and expression. Moreover, our results will generate protein candidates whose essential functions may be perturbed in hormone secreting tumors and thus contribute to resistance to SS analog therapy. Finally, they may suggest potential targets for drugs that act downstream of the sst2A receptor to bypass defects in receptor signaling and thus allow improved control of hormonal hypersecretion by pituitary tumors.

描述(由申请人提供)：G蛋白偶联受体家族的细胞表面表达、细胞内转运和信号转导受到许多与受体细胞质结构域相互作用的蛋白质的严格调控。这些受体相互作用蛋白(RIPs)的突变或表达改变破坏了锚定受体及其效应器的复合体，从而扰乱了受体的定位、运输和稳定性，并导致了受体信号的缺陷。一些RIPs已被证明与sst2A生长抑素(SS)受体结合，生长抑素类似物是SS类似物的治疗靶点，用于垂体和其他激素分泌神经内分泌肿瘤的主要药物治疗。SS类似物可减缓肿瘤进展并抑制生物活性肿瘤产物的分泌，从而控制由荷尔蒙分泌肿瘤产生的衰弱和潜在威胁生命的症状。不幸的是，SS类似物在很大一部分患者中无法控制激素的过度分泌。导致患者对SS类似物治疗反应性变化的因素尚不清楚，但不是sst2A受体突变的结果，也不能用sst2AmRNA表达的缺失来解释。这一应用的基本假设是，sst2A受体相互作用蛋白在激素分泌肿瘤对SS类似物的反应性中起关键作用，并且这些蛋白与sst2A受体的相互作用是动态调节的。在这项建议中，我们计划在垂体肿瘤细胞中鉴定与sst2A受体相关的蛋白质，并表征已识别的相互作用对sst2A受体细胞表面表达、细胞内转运的功能影响。和稳定性，以及其激活信号转导通路的能力，已知的信号转导通路介导SS抑制垂体激素的分泌。此外，我们将确定sst2A受体与其相互作用伙伴之间的联系是如何在细胞表面和胞内隔间动态调节的。拟议的研究将为控制sst2A受体信号、运输和表达的分子机制提供新的理解。此外，我们的结果将产生候选蛋白质，其基本功能可能在激素分泌肿瘤中受到干扰，从而导致对SS类似物治疗的抵抗。最后，他们可能为作用于sst2a受体下游的药物提供潜在的靶点，以绕过受体信号的缺陷，从而改善对脑垂体肿瘤激素过度分泌的控制。