Sufu-interacting proteins provide novel insight into mammalian Hedgehog signaling

 描述（由申请人提供）：本研究旨在填补我们对哺乳动物Hedgehog（Hh）信号传导机制理解的主要空白。Hh信号传导中断导致先天性异常和癌症发展。阻断Hh信号传导的药物已用于临床试验，用于治疗与异常Hh信号传导相关的人类癌症。我们在此应用中的研究集中在融合的抑制因子（Sufu），Hh信号传导的主要负调节因子。通过蛋白质组学的方法，使用腐乳作为工具，我们已经确定了新的球员Hh信号，包括p66 β和Mycbp。我们的初步研究采用获得和功能丧失的方法提供了强有力的证据，以支持一个模型，其中p66 β起着消极的作用，而Mycbp起着积极的作用，在调节Hh信号。我们还发现了一个新的水平的复杂性差异Hh反应通过分析腐乳突变体表型。这些发现为理解Hh信号是如何转导的提供了一个新的概念框架。基于这些新发现，我们将解决本应用中Hh信号传导的一个核心问题：如何通过调节Sufu和Gli功能产生分级Hh反应。我们的具体目标是（1）验证p66 β抑制和Mycbp增强Sufu在Hh信号转导中的核功能的假设;（2）研究p66 β和Mycbp调节Sufu在Hh信号转导中的分子机制;（3）研究Sufu和Hh应答对Gli蛋白的差异调节。总之，这些研究将提供新的见解哺乳动物Hh信号转导和Hh相关疾病的诊断和治疗奠定了基础。

 DESCRIPTION (provided by applicant): This study aims to fill a major gap in our mechanistic understanding of mammalian Hedgehog (Hh) signaling. Disrupted Hh signaling leads to congenital anomalies and cancer development. Drugs that block Hh signaling have been used in clinical trials for treating human cancers related to aberrant Hh signaling. Our research in thi application focuses on Suppressor of fused (Sufu), a major negative regulator of Hh signaling. Through a proteomic approach using Sufu as a tool, we have identified new players of Hh signaling, including p66ß and Mycbp. Our preliminary studies employing both gain- and loss-of function approaches provide strong evidence to support a model in which p66ß plays a negative role while Mycbp plays a positive role in regulating Hh signaling. We also uncovered a new level of complexity in differential Hh responses through analysis of Sufu mutant phenotypes. These findings offer a novel conceptual framework for understanding how the Hh signal is transduced. Based on these novel discoveries, we will address a central question of Hh signaling in this application: how graded Hh responses are produced through regulation of Sufu and Gli function. Our specific aims are (1) To test the hypothesis that p66ß inhibits and Mycbp potentiates Sufu's nuclear function in Hh signaling; (2) To investigate the molecular mechanisms by which p66ß and Mycbp regulate Sufu function in Hh signaling; and (3) To study differential regulation of Gli proteins by Sufu and Hh responses. Taken together, these studies will offer new insight into mammalian Hh signaling and establish the foundation for diagnosis and treatment of Hh-related diseases.