Network Interaction between EGFR and TGFbeta Pathways

EGFR 和 TGFbeta 通路之间的网络相互作用

• 批准号: 7032753
• 负责人: WILLIS X LI
• 金额: $ 24.02万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032753
• 关键词: Drosophilidae; arthropod genetics; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; developmental genetics; epidermal growth factor; gene expression; genetic enhancer element; genetic regulation; genetic regulatory element; growth factor receptors; membrane proteins; molecular biology; transforming growth factors

DESCRIPTION (provided by applicant): Signaling networks have increasingly emerged as the ruling principle in the control of complex biological processes. Cell proliferation and differentiation during normal development and tumor progression are regulated by multiple interacting signaling pathways, and it appears that specific biological responses often arise as the consequence of such interactions. Understanding the basic rules and the context in which these pathways interact thus has become a fundamental challenge for basic and cancer biology. In the following proposal we will use Drosophila as a highly genetically tractable in vivo model system to explore signaling network architecture and function. As a specific example, we will investigate the functionally important interactions between the epidermal growth factor receptor (EGFR) and transforming growth factor-6 (TGF6) pathways found in many developmental and pathological situations such as cell fate determination, differentiation, and tumor metastasis. In particular, we will study their interactions in controlling cell differentiation of Drosophila wing vein cells (a type of specialized epithelial cells). Our recent studies and those of others suggest that the two pathways not only upregulate each other's activities but are also both required for vein cell differentiation. In this proposal, we will focus on investigating how the EGFR and Dpp (a Drosophila homolog of TGF8) pathways reciprocally affect each other's activities and how they act together to instruct tissue differentiation. In this research proposal, we will test three main hypotheses: (1) the cell-autonomous EGFR-Dpp positive-feedback signaling cycle converts a transient and reversible signaling pathway activation to a self-sustainable and lasting "active state" of both pathways, which induces and maintains the irreversible process of cell differentiation, its coordination with cell cycle regulation, and the establishment of lateral inhibition, (2) the biological effects of the EGFR-Dpp signaling cycle are achieved in part by combinatorial transcription regulation of specific target genes, and (3) lateral inhibition by the Notch pathway is mediated via inhibition of the EGFR-Dpp cycle in intervein cells. Results from the proposed research will elucidate a novel mechanism of signaling crosstalk between the EGFR and Dpp pathways in a developmental context and should shed light on how these two signaling pathways cooperate in a variety of normal developmental as well as pathological situations such as tumor metastasis.

描述（由申请人提供）：信号网络越来越多地作为控制复杂生物过程的统治原则。在正常发育和肿瘤进展过程中的细胞增殖和分化受多种相互作用信号通路的调节，看来特定的生物学反应通常是由于这种相互作用的结果。因此，了解这些途径相互作用的基本规则和环境已成为基本和癌症生物学的基本挑战。在以下建议中，我们将使用果蝇作为一种高度遗传学的体内模型系统来探索信号网络架构和功能。作为一个特定的例子，我们将研究表皮生长因子受体（EGFR）与转化生长因子-6（TGF6）途径之间在许多发育和病理情况下发现的途径（例如细胞命运测定，分化和肿瘤转移）之间的功能重要相互作用。特别是，我们将研究它们在控制果蝇翼静脉细胞（一种专门上皮细胞）的细胞分化方面的相互作用。我们最近的研究和其他研究表明，这两种途径不仅上调了彼此的活动，而且都是静脉细胞分化所必需的。在此提案中，我们将重点研究EGFR和DPP（TGF8的果蝇同源物）途径如何相互影响彼此的活动以及它们如何共同行动以指导组织分化。 In this research proposal, we will test three main hypotheses: (1) the cell-autonomous EGFR-Dpp positive-feedback signaling cycle converts a transient and reversible signaling pathway activation to a self-sustainable and lasting "active state" of both pathways, which induces and maintains the irreversible process of cell differentiation, its coordination with cell cycle regulation, and the establishment of lateral inhibition, (2) the biological effects EGFR-DPP信号传导周期的一部分是通过对特定靶基因的组合调节的部分来实现的，（3）Notch途径横向抑制是通过互联细胞中EGFR-DPP循环抑制介导的。拟议的研究的结果将在发育环境中阐明EGFR和DPP途径之间信号传导串扰的新机制，并应阐明这两种信号通路如何在各种正常发育以及肿瘤转移等病理情况下合作。