CK2α通过磷酸化LATS1抑制YAP活性调控肝再生的作用及机制研究

YAP在肝再生过程中发挥重要作用。丝/苏氨酸蛋白激酶CK2α可通过YAP影响果蝇器官发育，但在哺乳动物中CK2α能否通过调控YAP影响肝再生过程尚不清楚。前期我们发现特异性敲低小鼠肝脏中CK2α可促进70%肝切除术后小鼠残肝再生。同时敲低CK2α可抑制小鼠残肝中的YAP磷酸化并上调YAP表达。进一步发现CK2α与YAP上游分子LATS1具有相互作用，且过表达CK2α能够上调LATS1丝/苏氨酸磷酸化水平，提示CK2α可能通过磷酸化LATS1调控YAP活性。在此基础上，本项目拟结合CK2α肝脏特异性敲除小鼠，进一步阐明CK2α在切除和损伤后小鼠肝再生过程中的功能，明确CK2α通过磷酸化LATS1调控YAP的分子机制，探究CK2α特异性小分子抑制剂对切除和损伤后小鼠肝再生的作用。本项目旨在明确CK2α在肝再生中的作用及机制，为发现新的促肝再生药物治疗提供理论基础。

YAP plays an important role during liver regeneration. Serine/threonine protein kinase CK2α can affect Drosophila organ development through modulating YAP. However, it is unclear whether CK2α can affect liver regeneration by regulating YAP in mammals. Our preliminary data showed that liver specific knockdown of CK2α promoted the regeneration processes in mice after 70% hepatectomy. Mechanistically, knocking down CK2α inhibited YAP phosphorylation and up-regulate YAP expression in the liver. We found that CK2α interacts with Lats1, an upstream kinases which regulates YAP activity. Furthermore, overexpression of CK2α can up-regulate the phosphorylation level of Lats1 serine/threonine, suggesting that CK2α may regulate YAP activity by phosphorylating Lats1. In the current study, we aim to clarify the function of CK2α during liver regeneration by using CK2α liver-specific knockout mice with hepatectomy model and liver injury models. We intend to elucidate the mechanisms of CK2α in regulating YAP through phosphorylated Lats1, and evaluate the specificity of CK2α small molecular inhibitors on liver regeneration. Altogether, our study will clarify the role and mechanism of CK2α during liver regeneration, and will provide a theoretical basis for the discovery of new drugs for promoting liver regeneration.