STUDIES OF PROTEINS THAT TRANDUCE HEDGEHOG SIGNALING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Hh蛋白的信号传导塑造了脊椎动物和无脊椎动物中许多组织和器官的发育。 在人类、绵羊、鱼类和小鼠胚胎中，Hh信号的减少会导致严重的前脑无裂畸形和独眼畸形（只有一只眼睛的形成）。 在成年人中，Hh信号对某些干细胞群至关重要，Hh信号的增加可导致皮肤癌、小脑癌、肌肉癌、消化道癌、胰腺癌和前列腺癌。 几种小分子Hh激动剂和拮抗剂目前正在开发中，并且作为有效药物具有很大的前景，但是Hh蛋白功能和信号传导的生物学是复杂的，并且仍然存在许多重要的问题。 了解Hh信号传导的机制和调节是一个具有直接医学意义的重要问题。 hh首先被鉴定为果蝇胚胎分割所需的基因，在我的小组和其他人对其进行分子分离之后，脊椎动物中的直系同源物也被分离和表征。 Hh的合成和加工对于其功能来说既复杂又重要。 在Hh接收细胞中，两种膜结合蛋白Ptc和Smoothened（Smo）介导Hh反应。 Ptc序列表明它是一种12跨膜蛋白，与细菌外排转运蛋白AcrB结构同源。 AcrB形成一个同源三聚体，泵出底物，包括胆汁酸及其衍生物;在这个时候，我们不知道如果Ptc共享任何功能同源性与AcrB，既不知道它的结构，也不知道其推定的底物特异性。 我们目前对访问CGL的计算资源的兴趣是由我们分析已鉴定的补丁蛋白大家族的保守性的愿望驱动的。 我们的目标是定义完整的家庭，确定保守的结构域和确定保守的结构域中的保守残基，以合理化的命名补丁蛋白质和指导功能的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Signaling by Hh proteins shapes the development of many tissues and organs in both vertebrates and invertebrates. In human, sheep, fish, and mouse embryos, reduced Hh signaling causes sever holoprosencephaly and cyclopia (the formation of only one eye). In human adults, Hh signaling is critical for certain stem cell populations, and increased Hh signaling can lead to cancers of the skin, cerebellum, muscle, digestive tract, pancreas, and prostate. Several small molecule Hh agonists and antagonists are currently in development and hold great promise as effective drugs, but the biology of Hh protein function and signaling is complex and many significant questions remain. Understanding the mechanism and regulation of Hh signaling is an important problem with immediate medical implications. hh was first identified as a gene that is required for segmentation of the Drosophila embryo, and subsequent to its molecular isolation by my group and others, orthologs in vertebrates were also isolated and characterized. Synthesis and processing of Hh is both complex and essential for its function. In Hh-receiving cells, two membrane-bound proteins, Ptc and Smoothened (Smo) mediate the Hh response. The Ptc sequence suggests that it is a 12-transmembrane protein with structural homology to the bacterial efflux transporter AcrB. AcrB forms a homotrimer that pumps out substrates that include bile acids and their derivatives; at this time, we do not know if Ptc shares any functional homology with AcrB, and neither its structure nor its putative substrate specificity is known. Our current interest in accessing the computational resources of the CGL is driven by our desire to analyze the conservation of the large family of Patched proteins that have been identified. Our goal is to define the complete family, identify conserved domains and identify conserved residues within the conserved domains in order to both rationalize the nomenclature for Patched proteins and to guide functional studies.