The Molecular Mechanisms that AxinFu-NT Encoded by AxinFu Allele Affects on Function of Wildtype Axin

Axin是一个多结构域的构架蛋白，它能通过与不同蛋白的相互作用调节不同的信号通路，其中包括Axin能通过促进b-catenin的降解下调Wnt信号；同源二聚化的Axin能通过MEKK1或MEKK4激活JNK磷酸化；Axin也能通过HIPK2激活p53第46位丝氨酸的磷酸化；最近的研究发现Axin还能通过Arkadia增加Smad7的降解增强TGF-b信号等。Axin通过对不同信号的调节参与调控生物个体发育、抑制肿瘤发生、参与细胞骨架重排等过程。鼠源Axin是由鼠的Fused（Fu）基因编码；AxinFu等位基因是由转座子IAP的插入产生的。AxinFu/Fu小鼠会出现胚胎致死、神经管分叉和不同...Axin is a multidomian scaffold protein, regulating many signaling pathways through interacting with different regulators. Axin can promote degradation of b-catenin to down-regualte Wnt signaling; homodimeric Axin can induce JNK activation through MEKK1 or MEKK4; Axin can also up-regulate HIPK2-mediated phosphorylation of p53 at Ser46. Through regulating multiple signaling pathways, Axin plays impo...学位：理学博士院系专业：生命科学学院生物医学科学系_生物化学与分子生物学学号：2162006015332

The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1, Acting as a Switch between Catabolism and Anabolism

林圣彩教授课题组长期致力于细胞信号转导的研究。近年来，该课题组潜心研究，不断攻关，取得了一系列重大成果，如揭示细胞如何应对生长因子缺乏的内在机理，发现了细胞自噬“路线图”、还发现了细胞如何感应“饥饿”信号AMP的信号传导通路等。其中，“发现细胞自噬‘路线图’”成果曾登上《科学》杂志，并入选2012年度“中国科学十大进展”。AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs