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.正常发育和肿瘤进展过程中的细胞增殖和分化是 由多种相互作用的信号通路调节，并且似乎特定的生物反应通常 是这种相互作用的结果。理解基本规则和这些规则的背景 因此，相互作用的途径已经成为基础生物学和癌症生物学的根本挑战。在以下 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来探索信号传导 网络结构和功能。作为一个具体的例子，我们将研究功能上重要的 表皮生长因子受体（EGFR）和转化生长因子-6（TGF-6）之间的相互作用 在许多发育和病理情况下发现的途径如细胞命运决定， 分化和肿瘤转移。特别地，我们将研究它们在控制细胞中的相互作用， 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 其他人的研究表明，这两种途径不仅相互上调对方的活动， 静脉细胞分化所需的。在本提案中，我们将重点关注如何表达EGFR和Dpp， （果蝇TGF-8的同源物）通路相互影响彼此的活动以及它们如何起作用 together一起to arbitratissue停止tissue组织differentiation分化.在本研究中，我们将测试三个主要假设：（1） 细胞自主EGFR-Dpp正反馈信号周期转换为瞬时和可逆信号 途径激活到两种途径的自我维持和持久的"活性状态"，其诱导和 维持细胞分化的不可逆过程，其与细胞周期调节的协调， 侧抑制的建立，（2）EGFR-Dpp信号传导循环的生物学效应在 部分通过特定靶基因的组合转录调节，和（3）Notch的侧向抑制 通过抑制脉间细胞的EGFR-Dpp循环介导。拟议的结果 研究将阐明EGFR和Dpp通路之间信号串扰的新机制， 发展背景，并应阐明这两个信号通路如何合作，在各种 正常发育以及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.