Hippo信号通路TEAD转录复合物的结构组装与功能调控

Hippo signaling pathway controls cell growth and organ size, which plays important roles in multiple biological processes such as tumorigenesis, tissue regeneration and stem cells. In mammalian Hippo pathway, MST1/2 suppresses growth by kinase cascade, whereas its downstream effector YAP/TAZ forms a "hybrid" transcription factor with TEAD to promote growth-related gene expression. Recently, we revealed the regulatory mechanism of MST1/2 SARAH domain on its activity. We identified VGLL4 as an antagonist of YAP, uncovered its mechanism on inhibition of YAP-TEAD activity, and designed a targeted inhibitory peptide mimicking VGLL4's function, which provides a new personal therapeutic strategy against human cancers with high YAP/VGLL4 ratio (Cancer Cell、Cell Res、J Biol Chem、J Struct Biol, 2014). This project will investigate the overall structure, dynamic assembly and functions of TEAD transcription complex to further reveal its precise regulatory mechanism. Combined with analysis of clinical sample, this study will elucidate the mechanism of tumorigenesis and provide structural basis and optional strategy for drug design and cancer therapy.

Hippo信号通路调控细胞生长和器官大小，在癌症发生、组织再生以及干细胞等方面发挥重要功能，近年来已成为多领域前沿热点。哺乳动物Hippo通路中，MST1/2等激酶通过级联反应转导生长抑制信号，而其下游YAP/TAZ则与TEAD结合形成"杂合"转录因子调控生长相关基因表达。我们前期工作阐明了MST1/2的C端寡聚结构域在其活性调控中的作用机制，发现了Hippo信号通路中原癌蛋白YAP的一个天然拮抗蛋白VGLL4，揭示了其功能机制，并设计发展了YAP的靶向抑制剂，为针对YAP/VGLL4比率失调的癌症提供一种新的个性化诊疗策略及途径（Cancer Cell、Cell Res、J Biol Chem、J Struct Biol）。本项目拟进一步从整体结构、动态组装、功能作用以及调控机制等方面深入研究TEAD转录复合物，并结合临床样本分析，阐释癌症发生机制，为相关药物设计与诊疗策略提供结构基础。

国际上，Hippo信号通路相关功能与机制研究已成为生命科学和医学领域的前沿热点。随着Hippo通路上游信号转导机制的不断明晰，人们开始进一步关注其下游效应子YAP与TEAD相互作用调控基因转录的方式与机制。于是TEAD相关转录复合物的功能作用和调控机制便成为重要研究热点。本项目研究旨在提供关于TEAD转录调控复合物的翔实结构信息和功能数据，建立TEAD转录复合物整体结构与组装调控模型，阐明TEAD相关复合物调控靶基因的作用机制，完善Hippo通路相关信号转导网络，丰富对炎症性肿瘤发病机理的认识，推动该领域发展。我们通过体外组装TEAD-DNA复合物，解析了TEAD复合物的整体三维结构。基于结构信息设计相互作用界面突变体，研究这些突变体对各组分相互作用的影响，找出影响结合的关键位点（位点1 R64/K65/I66/L68A和位点2 R95/K96/S100/Q103A）。在此基础上研究关键位点突变对细胞增殖的影响，阐明了TEAD转录复合物结构组装与功能调控的关系，建立其调控基因转录的机制模型，并为相关药物设计和诊疗策略研发提供基础。