Determinants of Smoothened Activity

平滑活动的决定因素

• 批准号: 6790100
• 负责人: ELIZABETH H WILLIAMS
• 金额: $ 4.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790100
• 关键词: Drosophilidae; RNA interference; alleles; biological signal transduction; cell surface receptors; chemical genetics; enzyme activity; genetic screening; kinesin; membrane proteins; phosphoprotein phosphatase; phosphorylation; postdoctoral investigator; protein binding; protein kinase; protein localization; protein protein interaction; protein purification; protein sequence; protein signal sequence; protein structure function; site directed mutagenesis; transcription factor

DESCRIPTION (provided by applicant): The Hedgehog (Hh) signaling pathway plays an essential and evolutionarily conserved role in patterning the embryonic body plan and in maintaining the proliferative status of adult cell populations. Inappropriate regulation of Hh signaling in vertebrates can lead to developmental defects and to multiple spontaneous and inherited cancers. One of the Hh pathway components implicated in the development of cancer is the transmembrane protein Smoothened (Smo). Smo is a primary determinant of Hh pathway activity, but the mechanism by which Smo mediates Hh signaling is not well understood. To identify the sequences necessary for Smo hyperphosphorylation, interaction with the downstream effector molecule Costal-2 (Cos2), and subcellular localization and to analyze the functional relevance of these events in Hh signaling, mutagenesis and biochemical characterization of Smo alleles will be conducted to map functional domains of Smo within its protein structure, and the cellular mediators of Smo phosphorylation will be identified and characterized through genetic and biochemical screening.

描述（由申请人提供）： Hedgehog (Hh) 信号通路在胚胎身体计划的形成和维持成体细胞群的增殖状态方面发挥着重要且进化上保守的作用。脊椎动物中 Hh 信号传导的不当调节可能导致发育缺陷以及多种自发性和遗传性癌症。与癌症发展有关的 Hh 通路成分之一是跨膜蛋白 Smoothened (Smo)。 Smo 是 Hh 通路活性的主要决定因素，但 Smo 介导 Hh 信号传导的机制尚不清楚。为了鉴定 Smo 过度磷酸化、与下游效应分子 Costal-2 (Cos2) 的相互作用和亚细胞定位所需的序列，并分析这些事件在 Hh 信号传导、诱变和 Smo 等位基因的生化特征中的功能相关性，以绘制图谱Smo 在其蛋白质结构中的功能域以及 Smo 磷酸化的细胞介质将通过遗传和生化筛选进行鉴定和表征。