Network Interaction between EGFR and TGFbeta Pathways

描述（由申请人提供）：信号网络越来越多地成为控制复杂生物过程的主导原则。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通常作为这种相互作用的结果而出现。因此，了解这些途径相互作用的基本规则和背景已经成为基础生物学和癌症生物学的一个根本挑战。在下面的建议中，我们将使用果蝇作为一个高度遗传易处理的体内模型系统，以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（TGF-6）途径之间的功能重要的相互作用，发现在许多发育和病理情况下，如细胞命运的决定，分化和肿瘤转移。特别是，我们将研究它们在控制果蝇翅静脉细胞（一种专门的上皮细胞）的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，这两个途径不仅上调对方的活动，但也都需要静脉细胞分化。在这个提议中，我们将集中研究EGFR和Dpp（一种果蝇TGF-8的同源物）通路如何相互影响对方的活动，以及它们如何共同作用以指导组织分化。在本研究中，我们将测试三个主要假设：（1）细胞自主的EGFR-Dpp正反馈信号传导循环将短暂和可逆的信号传导途径活化转化为两种途径的自我维持和持久的“活性状态”，其诱导并维持细胞分化的不可逆过程、其与细胞周期调节的协调以及侧向抑制的建立，（2）EGFR-Dpp信号循环的生物学效应部分地通过特定靶基因的组合转录调节实现，和（3）Notch途径的侧向抑制通过抑制脉间细胞中的EGFR-Dpp循环介导。拟议研究的结果将阐明EGFR和Dpp通路在发育背景下之间信号串扰的新机制，并应阐明这两种信号通路如何在各种正常发育和病理情况下（如肿瘤转移）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.