Analysis of Drosophila Kekkon1: an Inhibitor of the Epidermal Growth Factor Receptor

果蝇 Kekkon1 的分析：表皮生长因子受体的抑制剂

• 批准号: 0131707
• 负责人: Joseph Duffy
• 金额: $ 36万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0131707&HistoricalAwards=false
• 关键词: Analysis; Drosophila; Kekkon1; Inhibitor; Epidermal

0131707DuffyThe Epidermal Growth Factor Receptor (EGFR or ErbB) family of receptor tyrosine kinases has been implicated in a myriad of developmental decisions including mitogenesis, apoptosis, cellular migration, determination, differentiation, and dedifferentiation. Despite our knowledge of the role of this family in cellular decisions, our understanding of receptor activation and signal propagation is still in its infancy.The studies proposed by Dr. Duffy will use the model system, Drosophila melanogaster, to shed further light on the activation of EGFR signaling. This will be accomplished by dissecting the role of the inhibitory molecule, Kek1, in EGFR signaling. Kek1 encodes a transmembrane protein of the Leucine Rich Repeat (LRR) and Immunoglobulin (Ig) family that acts in a negative feedback loop to inhibit EGFR signaling. The availability of an abundance of genetic and molecular tools in Drosophila provide the means to decipher the mechanism of EGFR inhibition by Kek1 in vivo. This analysis will determine if Kek1 represents a new mode of inhibition and contribute to an improved understanding of EGFR signaling.The specific objectives proposed by Dr. Duffy are: (1) to define the mechanism through which Kek1 inhibits D-EGFR signaling by generating modified forms of Kek1. These constructs will by assayed biochemically, genetically, and molecularly for their effects on D-EGFR activity, both in vivo and in cell culture; (2) to define the residues of Kek1 and D-EGFR that mediate their interaction; and (3) to determine if Kek1's inhibitory function is conserved to the vertebrate receptors.To elucidate the role of the EGFR/ErbB family in development, a continuing effort must be made to characterize inhibitory molecules, such as Kek1.

0131707Duffy 受体酪氨酸激酶的表皮生长因子受体（EGFR 或 ErbB）家族涉及多种发育决策，包括有丝分裂、细胞凋亡、细胞迁移、决定、分化和去分化。尽管我们了解这个家族在细胞决策中的作用，但我们对受体激活和信号传播的理解仍处于起步阶段。Duffy 博士提出的研究将使用模型系统果蝇，进一步阐明 EGFR 信号传导的激活。 这将通过剖析抑制分子 Kek1 在 EGFR 信号传导中的作用来实现。 Kek1 编码富含亮氨酸重复序列 (LRR) 和免疫球蛋白 (Ig) 家族的跨膜蛋白，该蛋白在负反馈环中发挥作用，抑制 EGFR 信号转导。 果蝇中丰富的遗传和分子工具的可用性为破译 Kek1 在体内抑制 EGFR 的机制提供了手段。 该分析将确定 Kek1 是否代表了一种新的抑制模式，并有助于加深对 EGFR 信号传导的理解。 Duffy 博士提出的具体目标是：（1）通过生成 Kek1 的修饰形式来定义 Kek1 抑制 D-EGFR 信号传导的机制。这些构建体将在体内和细胞培养中通过生化、遗传学和分子学分析对 D-EGFR 活性的影响； (2) 定义介导Kek1和D-EGFR相互作用的残基； (3) 确定 Kek1 的抑制功能是否对脊椎动物受体保守。为了阐明 EGFR/ErbB 家族在发育中的作用，必须不断努力来表征抑制分子，例如 Kek1。