Growth regulation by the Fat signaling pathway

描述（由申请人提供）：本提案的目标是提供对组织生长和极性如何通过Fat-Hippo信号通路与模式化相关联的分子理解。这些研究将阐明这种新的细胞间信号通路的工作原理，该通路在正常发育和病理条件下调节生长。果蝇脂肪基因编码一个大的钙粘蛋白，作为脂肪信号的受体。两个基因已被确定为脂肪的调节因子：dachsous（ds），其编码充当脂肪配体的大钙粘蛋白，和四关节（fj），其编码高尔基体定位的激酶，其磷酸化脂肪和Ds的钙粘蛋白结构域以调节它们之间的结合。 Fat信号传导的一个显著特征是它可以通过一种独特的机制进行调节，该机制涉及响应Ds和Fj梯度的矢量和斜率，以影响影响平面细胞极性（PCP）和生长的不同下游过程。这些梯度抑制了细胞内的脂肪活性，如脂肪信号成分Dachs的定位所示。对这种新型信号通路调控的表征将为细胞行为的控制以及发育过程中模式化和生长如何联系起来提供新的见解。 该建议的第一个目的是探索脂肪途径的梯度传感的参数，使用遗传和细胞生物学操作的模型系统果蝇。第二个目标将描述和定义脂肪信号传导的初始步骤，包括脂肪对肌球蛋白Dachs的定位和活性的影响。第三个目标是研究最近发现的Fat-Hippo信号传导的正调控因子，以及Fat信号传导到Warts激酶的传递。这些研究将采用生物化学，细胞生物学和遗传学技术相结合的果蝇。 拟议的研究将提供对Fat-Hippo信号传导的分子基础的更深入的理解，Fat-Hippo信号传导是从果蝇到人类的重要和保守的生长调节剂。由于发育过程中的不适当生长导致器官大小或形状不正确，可能导致出生缺陷。控制器官生长对于理解干细胞如何用于修复或替换受损器官也很重要，这是再生医学的目标。此外，无法限制成熟生物体的生长导致癌症。多种器官中的癌症已经与Fat-Hippo信号传导的失活相关，包括肝、肾、皮肤、脑、肠、肺、卵巢、乳腺和前列腺。因此，了解Fat-Hippo信号的调节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.