Hedgehog Signaling in Development and Metabolism

摘要： Hhedgehog(HH)信号在模式形成和细胞生长控制中起着关键作用，也参与了 代谢控制。此外，异常的HH信号会导致多种类型的癌症。HH的转导 信号需要G蛋白偶联受体(GPCR)家族蛋白平滑(SMO)在昆虫和 哺乳动物。虽然已经确定了HH途径中的许多成分，但HH信号是如何被转导的 通过跨膜的12跨膜蛋白补丁(PTC)到Smo仍不清楚。该团队发现了1) 这种Smo经历了多个激酶的磷酸化，导致Smo细胞表面堆积和 信号活性；2)HH诱导的SUMO化促进Smo激活；3)泛素化 通过促进Smo内吞作用来下调Smo细胞表面的积聚。这些研究的结果 提示，对HH刺激的反应，在Smo的调节中发生了多个步骤。然而，尽管 重大进展，关于Smo蛋白表达的控制机制和关键问题仍然存在 激活：1)Smo转录是如何特异性调节的？2)HH是否以及如何调节脂解？ 3)胆固醇是如何激活Smo的？4)钠泵是否以及如何参与PTC和SMO 监管？该小组最近的发现是，Smo转录在脂肪组织中受到特异性调控， 另一种胆固醇生物合成途径调节Smo的积累和激活，并且 钠泵在激活Smo中起积极作用，可能是通过调节质膜上的胆固醇 是回答这些问题的关键基础。这项研究计划的首要目标是 了解HH信号是如何感知和传输的，以控制下游生物事件，最终 管理细胞生长和图案化。果蝇的脂肪体和卵母细胞已经成为吸引人的模型 研究脂肪代谢和循环。这些模型中已发表的和初步的发现表明 脂质的积累受到高度保守的信号通路的调节，HH信号不仅控制着 脂肪生成，但也通过调节特定基因进行脂肪分解。这些研究提供了新的工具和假设 研究Smo信号的机制及HH/Smo信号在调节脂质代谢中的作用， 这与基底细胞癌和髓母细胞瘤等癌症特别相关。建议的五项建议如下： 一年的研究计划使用遗传和生化方法的组合来建立在以前的基础上 并向新出现的调查途径过渡。从这项研究中获得的知识将 对PTC抑制Smo和胆固醇激活的机制提供新的见解。在……里面 此外，预期结果将为人类发育障碍提供新的见解，并促进 开发诊断工具和新的治疗方法来对抗Smo耐药性 代谢作为一个平台来改变当前癌症、肥胖和代谢中的HH信号的概念 疾病。

Abstract: Hedgehog (Hh) signaling plays critical roles in pattern formation and cell growth control and is also involved in metabolic control. Further, aberrant Hh signaling causes diverse types of cancers. Transduction of the Hh signal requires the G protein-coupled receptor (GPCR) family protein Smoothened (Smo) in both insects and mammals. While many components in the Hh pathway have been identified, how the Hh signal is transduced through the 12-span transmembrane protein Patched (Ptc) to Smo is still unclear. This team has discovered 1) that Smo undergoes phosphorylation by multiple kinases, which leads to Smo cell surface accumulation and signaling activity; 2) that sumoylation induced by Hh promotes Smo activation; and 3) that ubiquitination downregulates Smo cell surface accumulation by promoting Smo endocytosis. Results from these studies suggest that, in response to Hh stimulation, multiple steps occur in Smo regulation. However, despite significant progress, key questions persist regarding the mechanism controlling Smo protein expression and activation: 1) How is Smo transcription specifically regulated? 2) Whether and how does Hh regulate lipolysis? 3) How does cholesterol activate Smo? and 4) Whether and how is the sodium pump involved in Ptc and Smo regulation? Recent discoveries by this group that Smo transcription is specifically regulated in adipose tissue, that an alternative cholesterol biosynthesis pathway regulates Smo accumulation and activation, and that the sodium pump plays a positive role in activating Smo, likely by regulating cholesterol on the plasma membrane are critical foundations to answering those questions. The overarching goal of this research program is to understand how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. Drosophila fat body and oenocyte have emerged as attractive models to study lipid metabolism and circulation. Published and preliminary findings in these models have indicated that lipid accumulation is regulated by highly conserved signaling pathways, and that Hh signaling controls not only lipogenesis but also lipolysis by regulating specific genes. These studies provide new tools and hypotheses for investigating the mechanisms of Smo signaling and the role of Hh/Smo signaling in regulating lipid metabolism, which particular relevance to such cancers as basal cell carcinoma and medulloblastoma. The proposed five- year program of studies uses a combination of genetic and biochemical approaches to build on prior contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study will provide novel insights into mechanisms surrounding Smo suppression by Ptc and activation by cholesterol. In addition, expected outcomes will provide novel insights into human developmental disorders and promote development of diagnostic tools and novel therapeutic approaches to oppose Smo drug resistance using metabolism as a platform to transform current concepts of Hh signaling in cancer, obesity, and metabolic diseases.