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研究揭示Lats1/2维持肠道干细胞机制
2020-04-13 12:13
来源：小柯机器人

美国麻省大学医学院Junhao Mao、哈佛医学院Xu Wu等研究人员合作发现，Lats1/2通过TEAD依赖性和非依赖性转录来维持肠道干细胞并激活Wnt。2020年4月6日，《细胞—干细胞》在线发表了这一成果。

肠道动态平衡受复杂但未知的信号网络严格调控。研究人员证明，Hippo核心激酶Lats1/2对维持Wnt通路活性和肠干细胞至关重要。Lats1/2缺失会导致肠道干细胞丢失，但会导致Wnt无关的隐窝扩增。
 
为了探索TEAD（transcriptional enhanced associate domain）转录因子的功能下游，研究人员鉴定了选择性小分子可逆TEAD自棕榈酸酯化抑制剂，其直接占据脂质结合位点并在体内抑制TEAD介导的转录。
 
将这种化学工具与遗传和蛋白质组学方法相结合，研究人员显示Lat缺失对肠Wnt的抑制作用是YAP/TAZ依赖性的，但与TEAD无关。
 
从机制上讲，核内的YAP/TAZ与TLE（Groucho/Transducin-Like Enhancer of Split）相互作用，从而阻断TCF（Wnt/T-cell factor）介导的转录；对TEAD和Lats的双重抑制会抑制Wnt无关的Myc上调和APC（Adenomatouspolyposis coli）突变肠道的过度增殖。
 
这项研究表明，抑制TEAD棕榈酰化的药理学手段对靶向人类恶性肿瘤中的Wnt和Hippo信号传导具有重要意义。
 
附：英文原文

Title: Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription

Author: Qi Li, Yang Sun, Gopala K. Jarugumilli, Shun Liu, Kyvan Dang, Jennifer L. Cotton, Jordi Xiol, Pui Yee Chan, Michael DeRan, Lifang Ma, Rui Li, Lihua J. Zhu, Joyce H. Li, Andrew B. Leiter, Y. Tony Ip, Fernando D. Camargo, Xuelian Luo, Randy L. Johnson, Xu Wu, Junhao Mao

Issue&Volume: 2020-04-06

Abstract: Intestinal homeostasis is tightly regulated by complex yet poorly understood signalingnetworks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essentialto maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leadsto loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explorethe function of downstream transcriptional enhanced associate domain (TEAD) transcriptionfactors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylationthat directly occupies its lipid-binding site and inhibits TEAD-mediated transcriptionin vivo. Combining this chemical tool with genetic and proteomics approaches, we show thatintestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptionalactivator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically,nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to blockWnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Latssuppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatouspolyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approachto inhibit TEAD palmitoylation and have important implications for targeting Wnt andHippo signaling in human malignancies.

DOI: 10.1016/j.stem.2020.03.002

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30094-1

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
官方网址：https://www.cell.com/cell-stem-cell/home
投稿链接：https://www.editorialmanager.com/cell-stem-cell/default.aspx


本期文章：《细胞—干细胞》：Online/在线发表

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