Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription
Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription
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DOI：
10.1016/j.stem.2020.03.002
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发表时间：
2020-05-07
期刊：
影响因子：
23.9
通讯作者：
Mao, Junhao
中科院分区：
文献类型：
--
作者：
Li, Qi;Sun, Yang;Mao, Junhao
肠道内稳态受到复杂但知之甚少的信号网络的严格调节。在这里，我们证明了Lats 1/2，核心Hippo激酶，是维持Wnt通路活性和肠道干细胞所必需的。Lats 1/2缺失导致肠干细胞的丢失，但驱动Wnt-解偶联的隐窝扩增。为了探索下游转录增强相关结构域（TEAD）转录因子的功能，我们鉴定了一种选择性的TEAD自棕榈酰化可逆小分子抑制剂，其直接占据其脂质结合位点并抑制TEAD介导的体内转录。结合遗传和蛋白质组学的方法，我们表明，肠Wnt抑制Lats缺失是与PDZ结合结构域（TAZ）依赖，但TEAD独立的是的相关蛋白（雅普）/转录激活因子。在机制上，核雅普/TAZ与Grouchof-转导蛋白样分裂增强子（TLE）相互作用以阻断Wnt-细胞因子（TCF）介导的转录，并且TEAD和Lats的双重抑制抑制大肠腺瘤性息肉病（APC）突变的肠中的Wnt-解偶联Myc上调和上皮过度增殖，我们的研究强调了抑制TEAD棕榈酰化的药理学方法，并对靶向人类Wnt和Hippo信号传导具有重要意义。恶性肿瘤
Intestinal homeostasis is tightly regulated by complex yet poorly understood signaling networks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essential to maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leads to loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explore the function of downstream transcriptional enhanced associate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD autopalmitoylation that directly occupies its lipid-binding site and inhibits TEAD-mediated transcription in vivo. Combining this chemical tool with genetic and proteomics approaches, we show that intestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ interact with Grouchof-Transducin-Like Enhancer of Split (TLE) to block Wnta-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine, Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.