Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway
Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway
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DOI：
10.1016/j.celrep.2017.02.041
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发表时间：
2017-03-07
期刊：
影响因子：
8.8
通讯作者：
Hong, Wanjin
中科院分区：
文献类型：
--
作者：
Chakraborty, Sayan;Njah, Kizito;Hong, Wanjin
Hippo通路效应物雅普和TAZ作为响应细胞外基质（ECM）线索的机械信号的核传感器。然而，ECM中调节因子的身份和性质以及将机械反应信号传递到细胞内传感器的精确途径仍不清楚。在这里，我们发现了ECM蛋白聚糖聚集蛋白和转录辅激活因子雅普之间的功能联系。重要的是，聚集蛋白通过整合素-粘着斑-和Lrp 4/MuSK受体介导的信号传导途径转导基质和细胞刚性信号，增强雅普的稳定性和机械活性。聚集蛋白通过促进ILK-PAK 1信号传导和否定Merlin和LATS 1/2的功能来拮抗核心Hippo组分的粘着斑组装。我们进一步表明，聚集蛋白通过YAP依赖性转录促进肿瘤发生，并在人类肝癌中具有临床相关性。我们建议，聚集蛋白作为机械转导信号在ECM中。
The Hippo pathway effectors YAP and TAZ act as nuclear sensors of mechanical signals in response to extracellular matrix (ECM) cues. However, the identity and nature of regulators in the ECM and the precise pathways relaying mechanoresponsive signals into intracellular sensors remain unclear. Here, we uncover a functional link between the ECM proteoglycan Agrin and the transcriptional co-activator YAP. Importantly, Agrin transduces matrix and cellular rigidity signals that enhance stability and mechanoactivity of YAP through the integrin-focal adhesion-and Lrp4/MuSK receptor-mediated signaling pathways. Agrin antagonizes focal adhesion assembly of the core Hippo components by facilitating ILK-PAK1 signaling and negating the functions of Merlin and LATS1/2. We further show that Agrin promotes oncogenesis through YAP-dependent transcription and is clinically relevant in human liver cancer. We propose that Agrin acts as a mechanotransduction signal in the ECM.