2015年3月16日訊 /生物谷BIOON/ --近日，著名國際期刊nature cell biology同時在線發表了來自美國安德森癌症中心的陳俊傑教授和來自美國加州大學聖地牙哥分校的管坤良教授兩位華人科學家研究組關於AMPK調控Hippo信號通路的兩篇最新文章。
Hippo途徑是一條腫瘤抑制性信號通路，能夠對細胞增殖和凋亡起到調控作用。YAP是Hippo抑癌途徑中的一個轉錄共激活因子，對於控制細胞生長，組織穩態和器官大小具有重要作用。但關於調控Hippo途徑，控制器官大小預防癌症的上遊信號的相關研究仍然較少。
陳俊傑研究小組發現葡萄糖能夠調節Hippo途徑下遊效應因子YAP，而葡萄糖是細胞中ATP合成所需要的最普遍的能量來源。在細胞缺少葡萄糖的情況下，Hippo途徑和AMPK途徑都會發生激活，導致YAP發生磷酸化，促進其失活。他們同時發現GLUT3基因表達會受到YAP調控，參與葡萄糖代謝。陳俊傑研究小組的結果表明葡萄糖介導的能量平衡是參與Hippo途徑調控的一個上遊事件，同時YAP可通過促進糖酵解發揮癌基因功能，因此這項研究為葡萄糖代謝和Hippo途徑在組織維持和癌症預防方面提供了一個新的聯繫。
而管坤良教授在另一篇文章中指出，磷酸激酶Lats能夠對YAP進行磷酸化改變其細胞內定位，誘導YAP發生蛋白酶體降解，從而抑制YAP功能。YAP能夠通過結合TEAD轉錄因子家族誘導基因表達。Hippo-YAP途徑的紊亂常在人類腫瘤細胞中出現。他們發現細胞能量應激會誘導AMPK依賴性的Lats激活對YAP進行磷酸化，進而抑制YAP活性。通過進一步研究發現AMPK能夠直接對YAP ser94進行磷酸化，由於ser94對於YAP與TEAD結合至關重要，因此阻斷了YAP-TEAD的相互作用。AMPK阻斷YAP活性能夠抑制Lats缺失細胞中YAP高活性造成的致癌性轉化。這項研究建立了AMPK通過能量水平調節Hippo-YAP途徑的分子機制，證明了AMPK在調節該途徑方面的功能重要性。
綜上所述，兩篇文章同時發現能量平衡變化導致的AMPK對Hippo途徑中YAP的關鍵性調控，對於抑制YAP活性具有重要作用，對於治療YAP依賴性腫瘤具有重要意義。（生物谷Bioon.com）
AMPK modulates Hippo pathway activity to regulate energy homeostasis
Wenqi Wang,Zhen-Dong Xiao,Xu Li,Kathryn E. Aziz,Boyi Gan,Randy L. Johnson & Junjie Chen
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.
Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway
Jung-Soon Mo,Zhipeng Meng,Young Chul Kim,Hyun Woo Park, Carsten Gram Hansen, Soohyun Kim,Dae-Sik Lim & Kun-Liang Guan
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.