Growth regulation by the Fat signaling pathway

描述(由申请人提供)：本提案的目标是提供一个分子理解如何通过脂肪-河马信号通路将组织生长和极性与模式联系起来。这些研究将阐明这种新的细胞间信号通路的工作原理，它在正常发育和病理条件下调节生长。果蝇脂肪基因编码一种大的钙粘附素蛋白，作为脂肪信号的受体。有两个基因被确定为脂肪的调节基因：Dachsous(DS)，它编码一个大的钙粘附素，作为Fat的配体；以及四个关节(Fj)，它编码一个高尔基体定位的激酶，使Fat和D的钙粘素结构域磷酸化，调节它们之间的结合。脂肪信号的一个显著特征是，它可以由一种独特的机制调节，该机制涉及对DS和Fj梯度的矢量和斜率做出反应，以影响不同的下游过程，从而影响平面细胞极性(PCP)和生长。这些梯度极化了细胞内的脂肪活动，如脂肪信号成分DACH的定位所示。这种新形式的信号通路调控的特征将为控制细胞行为，以及模式和生长如何在发育过程中联系在一起提供新的见解。该提案的第一个目的是探索通过脂肪途径在模型系统黑腹果蝇中利用遗传和细胞生物学操作进行梯度传感的参数。第二个目标将描述和定义脂肪信号的初始步骤，包括脂肪对肌球蛋白Dachs定位和活性的影响。第三个目的是研究最近发现的Fat-Hippo信号的正调节因子，以及Fat信号到肌瘤的传递。这些研究将在果蝇身上使用生化、细胞生物学和遗传技术的组合。拟议的研究将提供更深入的了解脂肪-河马信号的分子基础，它是从果蝇到人类生长的重要和保守的调节因子。由于发育过程中不适当的生长导致器官大小或形状不正确，可能会导致出生缺陷。控制器官生长对于了解干细胞如何用于修复或替换受损器官也很重要，这是再生医学的一个目标。此外，无法限制成熟生物体的生长会导致癌症。许多器官的癌症与脂肪-河马信号的失活有关，包括肝、肾、皮肤、脑、肠、肺、卵巢、乳腺癌和前列腺癌。因此，了解Fat-Hippo信号的调控与一系列人类健康问题有关，包括出生缺陷、癌症和再生医学。

DESCRIPTION (provided by applicant): The goal of this proposal is to provide a molecular understanding of how tissue growth and polarity are linked to patterning by the Fat-Hippo signaling pathway. These studies will elucidate the workings of this novel intercellular signaling pathway, which regulates growth during both normal development and in pathological conditions. The Drosophila fat gene encodes a large cadherin protein that acts as a receptor for Fat signaling. Two genes have been identified as regulators of Fat: dachsous (ds), which encodes a large cadherin that acts as a ligand for Fat, and four-jointed (fj), which encodes a Golgi-localized kinase that phosphorylates cadherin domains of Fat and Ds to modulate binding between them. One remarkable feature of Fat signaling is that it can be regulated by a unique mechanism, which involves responding to the vector and slope of Ds and Fj gradients to influence distinct downstream processes that affect planar cell polarity (PCP) and growth. These gradients polarize Fat activity within cells, as visualized by the localization of the Fat signaling component Dachs. Characterization of this novel form of signaling pathway regulation will provide novel insights into the control of cell behavior, and how patterning and growth can be linked during development. The first aim of the proposal is to explore the parameters of gradient sensing by the Fat pathway, using genetic and cell biological manipulations in the model system Drosophila melanogaster. The second aim will characterize and define initial steps in Fat signaling, including the influence of Fat on the localization and activity of the myosin Dachs. The third aim investigates recently identified positive regulators of Fat-Hippo signlaing, and the transmission of Fat signaling to the kinase Warts. These studies will employ a combination of biochemical, cell biological, and genetic techniques in Drosophila. The proposed studies will provide a deeper understanding of the molecular basis for Fat-Hippo signaling, which is an important and conserved regulator of growth from Drosophila to humans. As inappropriate growth during development results in organs that are incorrectly sized or shaped, it can cause birth defects. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in mature organisms results in cancer. Cancers in a wide variety of organs have been associated with inactivation of Fat- Hippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate. Understanding the regulation of Fat-Hippo signaling is thus relevant to a range of human health issues, including birth defects, cancer, and regenerative medicine.