Network Interaction between EGFR and TGFbeta Pathways

描述(申请人提供)：信令网络日益成为控制复杂生物过程的主导原则。细胞在正常发育和肿瘤进展过程中的增殖和分化受到多条相互作用的信号通路的调节，并且似乎经常作为这种相互作用的结果而产生特定的生物学反应。因此，理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根本挑战。在下面的提案中，我们将使用果蝇作为一个高度遗传易控的活体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，我们将研究在许多发育和病理情况下发现的表皮生长因子受体(EGFR)和转化生长因子-6(TGF6)通路之间的重要功能相互作用，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果蝇翼静脉细胞(一种特化的上皮细胞)细胞分化过程中的相互作用。我们和其他人最近的研究表明，这两个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。在这个提案中，我们将重点研究EGFR和DPP(果蝇TGF8的同源物)通路如何相互影响彼此的活动，以及它们如何共同作用来指导组织分化。在本研究方案中，我们将检验三个主要假设：(1)细胞自主的EGFR-DPP正反馈信号周期将瞬时和可逆的信号通路激活转换为两个通路的自我持续和持久的“活性状态”，从而诱导和维持细胞分化的不可逆过程，与细胞周期调节相协调，并建立侧向抑制；(2)EGFR-DPP信号周期的生物学效应部分是通过对特定靶基因的组合转录调节来实现的；(3)Notch通路的侧向抑制是通过抑制静脉间细胞中的EGFR-DPP周期来实现的。这项研究的结果将阐明在发育背景下EGFR和DPP信号通路之间的信号串扰的新机制，并将阐明这两个信号通路在各种正常发育和病理情况下如何合作，如肿瘤转移。

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.