Cak调节hedgehog通路活性机制研究

Hedgehog（Hh）信号通路在动物发育及成体稳态维持中起必要作用，通路失调可导致发育缺陷及肿瘤发生。无Hh时，通路转录因子Ci与Cos2形成复合体，导致Ci羧基端一部分降解去除，形成截短形式的CiR抑制Hh通路活性；有Hh时，Hh促进Ci/Cos2复合体解聚抑制CiR形成，全长Ci入核激活Hh通路。Hh是如何促进Ci/Cos2复合体解聚而激活Hh通路的，这是领域内长期关注而未解决的问题。利用果蝇遗传学筛选，我们发现一个新的Hh通路调节激酶，命名为Cak。生化实验表明Hh促进Cos2招募Cak，导致Ci/Cos2复合体解聚，具体机制不清。本项目以果蝇为模式生物，研究Cak调节Hh通路分子机制。该研究具有重要理论意义，研究可能解释上述领域内长期未解决的问题；同时，搞清Cak调节机制有助于开发Hh通路相关癌症治疗的新策略，这对临床工作中针对性治疗具有重大意义。

Hedgehog (Hh) signaling pathway plays an essential role in animal development and adult homeostasis. Dysregulation of Hh pathway can lead to developmental defects and tumors. In the absence of Hh, the transcription factor Ci binds to Cos2, which results in the partial degradation of Ci and finally generating CiR，which inhibits Hh signaling activity. In the presence of Hh, Hh promotes the dissociation of Ci and Cos2 complex, and finally the full-length Ci enters the nucleus and activates the expression of Hh target genes. How Hh promotes the dissociation of Ci and Cos2 is a long-standing question in the field. Our genetic screening in Drosophila revealed that the kinase Cak regulates the activity of Hh Pathway. Biochemical experiments showed that Hh promotes recruitment of Cak by Cos2 and regulates the dissociation between Ci and Cos2. But the underlying mechanism is not clear. In this study, we will use Drosophila as a model to study the molecular mechanism of Cak regulating Hh signaling activity. This study will not only deepen our understanding of the regulation of Hh Pathway, but also help to develop new strategies for the treatment of Hh pathway-related cancers.