Structural Basis of Prolactin Receptor Recognition

催乳素受体识别的结构基础

• 批准号: 6922257
• 负责人: MICHAEL E HODSDON
• 金额: $ 29.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922257
• 关键词: biological signal transduction; cell surface receptors; chemical kinetics; gene mutation; hormone receptor; intermolecular interaction; molecular shape; nuclear magnetic resonance spectroscopy; phosphorylation; prolactin; protein isoforms; protein protein interaction; protein structure; receptor binding; site directed mutagenesis

DESCRIPTION (provided by applicant): The overall goal of this long-term project is to delineate the specific structural and functional interactions involved in prolactin receptor recognition and signal transduction. Although best known for its traditional role as a pituitary-derived hormone, recent research has established important autocrine/paracrine functions of prolactin in the growth and development of a diversity of tissues. Expression of prolactin and its cell-surface receptor has been demonstrated in multiple human breast and prostate cancer cell lines. Prolactin has mitogenic and angiogenic function in these tumors and increases cancer cell motility. The biology of peripheral prolactin synthesis is distinct from the pituitary, including alternative mechanisms for transcriptional regulation, RNA splicing, and hormone storage and secretion. Additionally, when isolated from peripheral tissue, or when produced by non-pituitary cell lines grown in culture, glycosylated and phosphorylated variants of prolactin are found. Research has demonstrated functional consequences of these modifications, some of which may act to counter the tumorigenic effects of native prolactin. Similarly, multiple isoforms of the prolactin receptor have been described in both healthy and malignant tissue. These receptor isoforms differ in their affinity for prolactin and in their activation of intracellular signal transduction pathways. The central hypothesis of this application states that distinct subsets of prolactin residues are responsible for the differences in recognition specificity displayed by prolactin and its variants towards prolactin receptor isoforms. We will use NMR spectroscopy to identify, at an atomic level, the precise intermolecular interactions responsible for receptor recognition specificity. The functional significance of these interactions will be investigated by measurement of receptor binding kinetics and assays of cellular activation and signal transduction. By comparison of the wild type and variant forms of prolactin, we hope to uncover the molecular mechanisms for both receptor agonism and antagonism. The results of the proposed research will aid the development of potential therapeutic agents designed to modulate specific activities of prolactin, including prolactin receptor antagonists, which will have significance for the treatment of breast, prostate and, potentially, other cancers.

描述（由申请人提供）：该长期项目的总体目标是描述催乳素受体识别和信号转导中涉及的特定结构和功能相互作用。虽然最为人所知的是其作为垂体衍生激素的传统作用，但最近的研究已经确定了催乳素在多种组织的生长和发育中的重要自分泌/旁分泌功能。催乳素及其细胞表面受体的表达已在多种人乳腺癌和前列腺癌细胞系中得到证实。催乳素在这些肿瘤中具有促有丝分裂和血管生成功能，并增加癌细胞的运动性。外周催乳素合成的生物学不同于垂体，包括转录调节、RNA剪接和激素储存和分泌的替代机制。此外，当从外周组织中分离时，或者当由培养中生长的非垂体细胞系产生时，发现了催乳素的糖基化和磷酸化变体。研究已经证明了这些修饰的功能后果，其中一些可能会对抗天然催乳素的致瘤作用。同样，催乳素受体的多种亚型在健康和恶性组织中均有描述。这些受体亚型的不同之处在于它们对催乳素的亲和力和它们对细胞内信号转导途径的激活。 本申请的中心假设指出，催乳素残基的不同子集是催乳素及其变体对催乳素受体亚型显示的识别特异性差异的原因。我们将使用核磁共振光谱法在原子水平上识别负责受体识别特异性的精确分子间相互作用。这些相互作用的功能意义将通过测量受体结合动力学和测定细胞活化和信号转导来研究。通过比较催乳素的野生型和变异形式，我们希望揭示受体激动和拮抗的分子机制。拟议研究的结果将有助于开发旨在调节催乳素特定活性的潜在治疗药物，包括催乳素受体拮抗剂，这将对乳腺癌，前列腺癌和其他癌症的治疗具有重要意义。