Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium

描述（由申请人提供）：刺猬通路是控制哺乳动物细胞行为的基本手段之一，用于调节各种不同的生物事件，包括组织模式，干细胞更新和细胞增殖。从果蝇到小鼠，所有生物中的刺猬信号都依赖于原癌基因Smoothened，这种突变可导致基底细胞癌（北美最常见的癌症）和成神经管细胞瘤（儿童中最常见的实体癌）。尽管Smoothened对发育和疾病都很重要，但其功能的分子机制尚不清楚。我们最近发现哺乳动物的刺猬信号平滑地移动到一种叫做初级纤毛的细胞器，这种移动对于平滑的活动是必要的。虽然已知几乎所有哺乳动物细胞都有一个延伸到细胞外环境的初级纤毛，但人们对这种细胞器的功能知之甚少。我们提出初级纤毛作为细胞天线，通过它传导Hedgehog信号。我们试图在这些发现的基础上研究Smoothened如何作用于纤毛，以及纤毛是否参与Smoothened介导的癌症发展。具体来说，我们将回答四个问题：1)Smoothened向主纤毛的运输是如何调节的？Smoothened是如何激活纤毛通路的？3)平滑定位在癌症中是否失调？4)平滑介导的肿瘤发生需要原发纤毛吗？提出的实验使用遗传、分子和生化方法来回答正常细胞、人类肿瘤和小鼠癌症模型中的这些问题。本研究旨在阐明纤毛平滑调节的机制，评估纤毛在发育和肿瘤发生中的功能。综上所述，这些研究将提供对平滑纤毛和初级纤毛在发育和疾病中如何调节Hedgehog信号转导的生化和细胞生物学理解。

DESCRIPTION (provided by applicant): The Hedgehog pathway is one of the fundamental means of controlling mammalian cell behavior and is used to regulate a wide variety of disparate biological events including tissue patterning, stem cell renewal, and cell proliferation. All Hedgehog signaling in organisms ranging from Drosophila to mice relies on the proto-oncogene Smoothened, mutations in which can cause basal cell carcinoma, the most common cancer in North America, and medulloblastoma, the most common solid cancer among children. Despite its importance to both development and disease, the molecular mechanism by which Smoothened functions remains unclear. We have recently discovered that mammalian Hedgehog signals move Smoothened to an organelle called the primary cilium, and that this movement is necessary for Smoothened activity. Although it is known that almost all mammalian cells possess a single primary cilium that extends into the extracellular environment, the functions of this organelle are poorly understood. We propose that the primary cilium acts as a cellular antenna, through which Hedgehog signals are transduced. We seek to build on these findings to investigate how Smoothened acts at the cilium and whether cilia participate in Smoothened-mediated cancer development. Specifically, we will answer four questions: 1) How is the transport of Smoothened to the primary cilium regulated? 2) How does Smoothened activate its pathway at the cilium? 3) Is Smoothened localization misregulated in cancer? 4) Are primary cilia required for Smoothened-mediated oncogenesis? The proposed experiments use genetic, molecular, and biochemical approaches to answer these questions in normal cells, human tumors, and mouse cancer models. This work will both elucidate the mechanism of Smoothened regulation, and assess the function of primary cilia in development and neoplasia. Taken together, these studies will provide a biochemical and cell biological understanding of how Smoothened and the primary cilium regulate Hedgehog signal transduction both in development and in disease.