Genetic Analysis of Intracellular Signaling Crosstalk

描述（由申请方提供）：受体酪氨酸过度活化 RTKs与许多癌症或其他人类疾病有关。一个 一个重要的悬而未决的问题是，持续激活RTK如何能够引发 异常的细胞反应根据我们的初步研究，我们建议， RTK在过度激活时，不仅过度刺激其自身的典型途径， 而且还引起非典型路径的串扰或交叉激活。 我们用果蝇，一种遗传学上易于处理的模式生物，来研究信号传递 体内串扰躯干（Tor）是一种经过充分研究的飞行RTK，与 哺乳动物PDGF受体，其通过Ras-MAPK途径发出信号。我们最近 令人惊讶的发现，一种功能获得性（GOF）突变体Tor（TorGOF） 通过STAT蛋白Mrl引起异位基因表达模式， 基因marelle（mrl; a.k.a. DStat 92 E），和一种新的蛋白质TIw，由一种 我们将该基因命名为tail low（tlw）。在这里，我们建议调查的机制， 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 RTK能够激活非经典途径，它很少在低水平参与。 信号强度或生理条件下。在该模型中，野生型 Tor主要通过Ras/Raf/MEK/MAPK在细胞内进行信号转导 信号盒然而，TorGOF另外激活Mrl，并且可能 引发病理反应。这项工作的结果应该有助于阐明 信号串扰的机制，这可能是重要的人类 发病机制以及肿瘤发生。

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.