Mo Jung-Soon, Meng Zhipeng, Kim Young Chul, Park Hyun Woo, Hansen Carsten Gram, Kim Soohyun, Lim Dae-Sik, Guan Kun-Liang
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Department of Cardiology, Veterans Medical Research Foundation, 3350 La Jolla Village Dr., San Diego, California 92161, USA.
Nat Cell Biol. 2015 Apr;17(4):500-10. doi: 10.1038/ncb3111. Epub 2015 Mar 9.
YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway.
YAP（Yes相关蛋白）是河马肿瘤抑制通路中的一种转录共激活因子，可控制细胞生长、组织稳态和器官大小。YAP被激酶Lats抑制，Lats使YAP磷酸化以诱导其细胞质定位和蛋白酶体降解。YAP通过与TEAD家族转录因子结合来诱导基因表达。在人类癌症中经常观察到河马 - YAP通路的失调。在这里，我们表明细胞能量应激会诱导YAP磷酸化，部分原因是AMPK依赖性的Lats激活，从而抑制YAP活性。此外，AMPK直接磷酸化YAP的Ser 94，这是与TEAD相互作用所必需的一个残基，从而破坏YAP - TEAD相互作用。AMPK诱导的YAP抑制可抑制具有高YAP活性的Lats缺失细胞的致癌转化。我们的研究确立了AMPK在将细胞能量状态与河马 - YAP通路联系起来方面的分子机制和功能意义。
