筛选和鉴定Hippo信号转导途径中抑制Hippo蛋白激酶活性的新成员

Hippo(Hpo)信号通路是近年来发现的在物种间非常保守的肿瘤抑制信号通路，能通过抑制细胞增殖，促进细胞凋亡来调控器官发育的大小。已有研究证明，Hpo通路直接调控了肿瘤的发生及干细胞的增殖发育。Hpo激酶作为Hpo通路中激酶复合物的核心，其活性调节机制一直知之甚少。通过大规模遗传学筛选，并结合分子、生化、遗传等手段进行分离、鉴定，首次发现了参与细胞极性维持的Par-1激酶，能通过直接磷酸化Hpo抑制其激酶活性，并同时调控了Hpo激酶复合物的稳定性，进而抑制了Hpo信号，促进了组织器官的生长，是一个潜在的原癌基因。我们将利用体外实验和动物模型，阐明Par-1调控Hpo活性的机制，同时揭示细胞极性与Hpo信号的调控关系。由于Hpo信号通路的活性异常与癌症的发生密切相关，本研究不仅能回答发育生长调控的基本问题，还将有助于我们认识癌症发生的分子机理，为人类癌症的诊断和治疗提供理论基础和新的思路。

Hippo pathway is emerging as a highly conserved tumour suppressor pathway. Studies over the past decade have uncovered that Hippo pathway controls organ size during development by balancing cell proliferation and apoptosis. It also has been reported that, Hippo pathway coordinates with other known pathways that involve cell fate decision to regulate tumorigenesis and stem cell proliferation and differentiation. Although the signaling of the core kinase cascade is relatively well understood, less is known about the upstream inputs and regulation mechanism of the Hippo kinase activity. By large scale genetic screening and analyses using molecular and cellular techniques, we identify and uncover the Par-1 polarity kinase as a negative regulator of Hippo. Par-1 inhibits Hippo kinase activity by direct mono-phosphorylation, and also regulates the stability of core kinase complex of Hippo signaling to suppress Hippo signaling, leading to organ growth, which makes it a potential oncogene. By using in vitro experiments and animal models, we are going to expound the regulation mechanism of Hippo kinase activity by Par-1 and hence uncover the regulatory relationship between cell polarity and Hippo signaling. Considering the close relationship between malfunction of Hippo signaling and tumorigenesis, our research may not only help to uncover the basic principle of growth control during development, but also enrich our understanding of the molecular mechanism of tumorigenesis, and hence provide new ideas for diagnosis and treatment of human cancers.