Network Interaction between EGFR and TGFbeta Pathways

信号网络越来越多地成为控制复杂生物的主导原则 流程。细胞在正常发育和肿瘤进展过程中的增殖和分化 受多个相互作用的信号通路调节，而且似乎特定的生物反应通常 作为这种互动的结果而出现。理解基本规则和这些规则的背景 因此，通路相互作用已成为基础生物学和癌症生物学的根本挑战。在以下内容中 建议我们将果蝇作为一种高度遗传易控的体内模型系统来探索信号转导 网络架构和功能。作为一个具体的例子，我们将研究在功能上重要的 表皮生长因子受体与转化生长因子-6的相互作用 在许多发育和病理情况下发现的通路，如细胞命运决定， 分化和肿瘤转移。特别是，我们将研究它们在控制细胞过程中的相互作用 果蝇翅静脉细胞(一种特化上皮细胞)的分化我们最近的研究和 另一些人认为，这两条途径不仅相互促进对方的活动，而且两者都是 在这个方案中，我们将重点研究EGFR和DPP是如何 (果蝇TGF8的同源物)通路相互影响彼此的活动以及它们如何起作用 一起指示组织分化。在这项研究方案中，我们将检验三个主要假设：(1) 细胞自主的EGFR-DPP正反馈信号周期转换为瞬时和可逆的信号 通路激活到两个通路的自我维持和持久的“活跃状态”，从而诱导和 维持不可逆的细胞分化过程及其与细胞周期调节的协调，以及 建立侧向抑制，(2)EGFR-DPP信号循环的生物学效应在 部分是通过特定靶基因的组合转录调控，以及(3)Notch的侧向抑制 这一途径是通过抑制静脉间细胞中的EGFR-DPP循环来实现的。建议的结果 研究将阐明EGFR和DPP通路之间信号串扰的一种新机制 并应该阐明这两个信号通路如何在不同的 正常发育和病理情况，如肿瘤转移。

Signaling networks have increasinglyemerged as the ruling principlein the control of complex biological processes. Cell proliferation and differentiation duringnormal 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. Understandingthe 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 upregulateeach other's activities but are also both required for vein cell differentiation.In this proposal, we will focus on investigatinghow the EGFR and Dpp (a Drosophila homolog of TGF8) pathways reciprocallyaffect each other's activities and how they act together to instructtissue differentiation. In this research proposal, we will test three main hypotheses: (1) the cell-autonomous EGFR-Dpp positive-feedback signalingcycle converts a transient and reversiblesignaling 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 inhibitionof the EGFR-Dpp cycle in intervein cells. Results from the proposed research will elucidate a novel mechanism of signalingcrosstalk 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.