Network Interaction between EGFR and TGFbeta Pathways

描述（由申请人提供）：信号网络在复杂生物过程的控制中日益成为主导原则。在正常发育和肿瘤进展过程中，细胞增殖和分化受到多种相互作用的信号通路的调节，并且似乎特定的生物反应往往是这些相互作用的结果。因此，了解这些途径相互作用的基本规则和背景已成为基础生物学和癌症生物学的基本挑战。在下面的建议中，我们将使用果蝇作为一个高度遗传可处理的体内模型系统来探索信号网络的结构和功能。作为一个具体的例子，我们将研究表皮生长因子受体（EGFR）和转化生长因子-6 （TGF6）途径在许多发育和病理情况下（如细胞命运决定、分化和肿瘤转移）的重要功能相互作用。特别是，我们将研究它们在控制果蝇翼静脉细胞（一种特化上皮细胞）细胞分化中的相互作用。我们最近的研究和其他人的研究表明，这两种途径不仅相互上调活性，而且都是静脉细胞分化所必需的。在本提案中，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性，以及它们如何共同作用以指导组织分化。在本研究计划中，我们将检验三个主要假设：(1)细胞自主EGFR-Dpp正反馈信号周期将短暂可逆的信号通路激活转化为两条通路的自我持续持久的“激活状态”，诱导和维持细胞分化的不可逆过程，其与细胞周期调节的协调，并建立侧抑制；(2) EGFR-Dpp信号周期的生物学效应部分是通过特异性靶基因的组合转录调控实现的；(3)Notch通路的横向抑制是通过抑制静脉间细胞中的EGFR-Dpp周期来介导的。本研究的结果将阐明EGFR和Dpp信号通路在发育背景下的信号串扰新机制，并阐明这两种信号通路在各种正常发育和病理情况（如肿瘤转移）中如何合作。

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.