Regulation of somatostatin receptor signaling

生长抑素受体信号传导的调节

• 批准号: 8495448
• 负责人: AGNES SCHONBRUNN
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495448
• 关键词: Address; Affect; Affinity; Agonist; Antibodies; Arrestins; Bar Codes; Binding; Biochemical Markers; Biochemical Process; Biological; Biology; Carcinoid Tumor; Cell Line; Cell membrane; Cell physiology; Cells; Characteristics; Clinical; Clinical Trials; Complement; Coupled; Development; Drug Delivery Systems; Effectiveness; Environment; Enzymes; Event; Family; Foundations; Funding; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gastrointestinal Hormones; Goals; Hormonal; Hormones; Human; Individual; Intervention; Knowledge; Lead; Life; Ligands; Modeling; Molecular; Multienzyme Complexes; Nature; Neuroendocrine Cell; Neuroendocrine Tumors; Normal tissue morphology; Occupations; Octreotide; Pancreatic Hormones; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Pituitary Gland; Pituitary Hormones; Pituitary Neoplasms; Play; Process; Protein Dephosphorylation; Protein Isoforms; Proteins; Receptor Signaling; Recycling; Regulation; Resistance; Resistance development; Role; SOM-230; Second Messenger Systems; Series; Signal Pathway; Signal Transduction; Site; Somatostatin; Somatostatin Analog Therapy; Somatostatin Receptor; Sorting - Cell Movement; Tail; Testing; Therapeutic; Time; Tissues; Transmembrane Domain; Tumor Tissue; Work; analog; base; cancer diagnosis; cell type; desensitization; effective therapy; improved; insight; neoplastic cell; novel; prevent; prototype; receptor; receptor binding; receptor function; receptor internalization; research study; response; second messenger; somatostatin analog; therapeutic target; therapy resistant; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): Regulation of somatostatin receptor signaling (Schonbrunn) Somatostatin (SS) receptor 2A (sstr2A) is the most widely expressed SS receptor subtype in normal tissues and human tumors. It plays a critical physiological role in regulating pituitary, pancreatic and gastrointestinal hormone secretion, among many biological actions. It is also the therapeutic target for the SS analogs used to treat patients with pituitary and gastro-enteropancreatic neuroendocrine tumors in order to inhibit hormonal hyper-secretion and to reduce tumor growth. Unfortunately, a large fraction of patients are resistant to SS analog therapy from the start and others develop resistance during the course of treatment. The reasons for this are unknown. To increase our understanding of SS action and improve its therapeutic applications our long term goal is to elucidate the molecular events involved in SS receptor signaling and the mechanisms which regulate receptor function to produce target cell resistance. Our previous studies showed that hormone binding stimulates the rapid and specific phosphorylation of sstr2A at multiple Ser and Thr, which we have identified. Receptor phosphorylation alters both sstr2A signaling and subcellular trafficking, with specific phosphorylation sites exerting distinct effects on receptor function. Unexpectedly, the pattern of receptor phosphorylation varies dramatically with different ligands, including those currently in clinical trials. The objective of this proposal is to determine how the phosphorylation of sstr2A i controlled and how it affects receptor signaling and trafficking. The organizing hypothesis for these studies is that phosphorylation and dephosphorylation of sstr2A are stringently regulated in order to produce receptors with distinct patterns of phosphorylated residues - a so-called phosphorylation "bar code". We propose that these differentially phosphorylated receptors are generated in different cellular compartments and determine the interactions of the receptor with specific cytosolic proteins that then produce the cellular response to SS and SS analog stimulation. This hypothesis will be tested in four specific aims: (1) Determine how phosphorylation of specific Ser/Thr residues affects sstr2A trafficking and signaling, (2) Identify the enzymes that regulate the phosphorylation state of the receptor. We will complete the identification of the kinases that phosphorylate sstr2A and will characterize the enzyme complexes that catalyze sstr2A dephosphorylation in a phosphosite- specific manner. We will also determine how specific phosphatases are directed to act on the receptor in particular subcellular compartments, (3) Elucidate the mechanisms that produce cell-type specific differences in sstr2A phosphorylation, trafficking, and signaling in pituitary and gastroenteropancreatic tumor cells, and (4) Elucidate the mechanisms responsible for agonist-specific sstr2A trafficking and desensitization. These studies will provide novel insights into the biochemical and cellular processes which regulate sstr2A, as well as other G protein coupled receptors, and the manner in which different agonists and the cellular environment impact those processes.

描述（由申请人提供）：生长抑素受体信号传导的调节（Schonbrunn） 生长抑素（SS）受体2A（sstr2A）是正常组织和人类肿瘤中表达最广泛的SS受体亚型。它在调节垂体、胰腺和胃肠道激素分泌等多种生物学作用中发挥着重要的生理作用。它也是用于治疗垂体和胃肠胰神经内分泌肿瘤患者的 SS 类似物的治疗靶点，以抑制激素过度分泌并减少肿瘤生长。不幸的是，很大一部分患者从一开始就对 SS 类似物治疗产生耐药性，而其他患者则在治疗过程中产生耐药性。其原因尚不清楚。为了增加我们对 SS 作用的理解并改善其治疗应用，我们的长期目标是阐明 SS 受体信号传导涉及的分子事件以及调节受体功能以产生靶细胞抵抗的机制。我们之前的研究表明，激素结合会刺激 sstr2A 在多个 Ser 和 Thr 上快速且特异性的磷酸化，我们已经确定了这一点。受体磷酸化会改变 sstr2A 信号传导和亚细胞运输，特定磷酸化位点对受体功能产生不同的影响。出乎意料的是，受体磷酸化模式随着不同配体（包括目前处于临床试验中的配体）的不同而显着变化。该提案的目的是确定 sstr2A 的磷酸化是如何控制的以及它如何影响受体信号传导和运输。这些研究的组织假设是 sstr2A 的磷酸化和去磷酸化受到严格调节，以产生具有不同磷酸化残基模式的受体 - 所谓的磷酸化“条形码”。我们提出这些差异磷酸化的受体在不同的细胞区室中产生，并确定受体与特定胞质蛋白的相互作用，然后产生对 SS 和 SS 类似物刺激的细胞反应。该假设将在四个具体目标中进行检验：(1) 确定特定 Ser/Thr 残基的磷酸化如何影响 sstr2A 运输和信号转导，(2) 识别 调节受体磷酸化状态的酶。我们将完成对 sstr2A 磷酸化激酶的鉴定，并将表征以磷酸位点特异性方式催化 sstr2A 去磷酸化的酶复合物。我们还将确定特定磷酸酶如何定向作用于特定亚细胞区室中的受体，(3) 阐明在垂体和胃肠胰腺肿瘤细胞中 sstr2A 磷酸化、运输和信号传导中产生细胞类型特异性差异的机制，以及 (4) 阐明激动剂特异性 sstr2A 运输和脱敏的机制。这些研究将提供新的见解 调节 sstr2A 以及其他 G 蛋白偶联受体的生化和细胞过程，以及不同激动剂和细胞环境影响这些过程的方式。