Genetic Analysis of Intracellular Signaling Crosstalk

描述(申请人提供)：受体酪氨酸过度激活 激酶(RTK)与许多癌症或其他人类疾病有关。一个 重要的悬而未决的问题是，持续激活的RTK如何引发 异常的细胞反应。根据我们的初步研究，我们建议 当RTK被过度激活时，不仅过度刺激自己的规范途径， 而且还带来了非正则通路的串扰或交叉激活。 我们使用果蝇，一种遗传上易驯化的模式生物，来研究信号 活体内的相声。Torso(Tor)是一种研究得很好的Fly RTK，与 哺乳动物的PDGF受体，通过Ras-MAPK途径传递信号。我们最近 一个令人惊讶的发现，一个功能获得(GOF)突变体Tor(TorGOF) 通过STAT蛋白MRL引起异位基因表达模式，由 基因Marelle(MRL；又名：Marelle(MRL；又名DStat92E)和一种新的蛋白TIW，该蛋白由一种 基因，我们命名为尾巴低(TLW)。在这里，我们建议研究一下 从TorGOF到其他信号通路的串扰通过遗传和 生化手段。我们将测试我们的假设，在高信号强度下 RTK能够激活它在低谷很少参与的非正则通路 信号强度或在生理条件下。在此模型中，通配型 Tor信号转导主要通过细胞内Ras/Raf/MEK/MAPK途径 信号录像带。然而，TorGOF额外激活了MRL，并可能 TLW诱导病理反应。这项工作的结果应该会给我们带来一些启示 关于可能对人类很重要的信号串扰的机制 发病机制以及肿瘤的发生。

DESCRIPTION (provided by applicant): Overactivation of receptor tyrosine kinases (RTKs) has been linked to many cancers or other human diseases. An important unanswered question is how persistently activated RTK can elicit abnormal cellular responses. Based on our preliminary studies, we propose that an RTK, when overactivated, not only overstimulates its own canonical pathway, but also brings about crosstalk or crossactivation of non-canonical pathways. We use Drosophila, a genetically tractable model organism, to study signaling crosstalk in vivo. Torso (Tor) is a well studied fly RTK most homologous to the mammalian PDGF receptor that signals through the Ras-MAPK pathway. We recently made a surprising discovery that a gain-of-function (GOF) mutant Tor (TorGOF) causes ectopic gene expression patterns via the STAT protein Mrl, encoded by the gene marelle (mrl; a.k.a. DStat92E), and a novel protein TIw, encoded by a gene we named tail low (tlw). Here we propose to investigate the mechanisms of the crosstalk from TorGOF to other signaling pathways by genetic and biochemical means. We will test our hypothesis that at high signaling intensity RTK is able to activate non-canonical pathways that it rarely engages at low signaling intensity or under physiological conditions. In this model, wildtype Tor transduces signals mainly through the Ras/Raf/MEK/MAPK intracellular signaling cassette. TorGOF, however, additionally activates Mrl and possibly Tlw to induce a pathological response. Results from this work should shed light on the mechanisms of signaling crosstalk that may be important for human pathogenesis as well as tumorigenesis.