Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway

被引:199
作者
Chakraborty, Sayan [1 ]
Njah, Kizito [1 ]
Pobbati, Ajaybabu V. [1 ]
Lim, Ying Bena [2 ]
Raju, Anandhkumar [1 ]
Lakshmanan, Manikandan [1 ]
Tergaonkar, Vinay [1 ]
Lim, Chwee Teck [2 ,3 ,4 ]
Hong, Wanjin [1 ]
机构
[1] ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore
[2] Singapore MIT Alliance Res & Technol, Infect Dis Interdisciplinary Res, 1 Create Way, Singapore 138602, Singapore
[3] Natl Univ Singapore, Dept Biomed Engn, 4 Engn Dr 3, Singapore 117583, Singapore
[4] Natl Univ Singapore, Mechanobiol Inst, 5A Engn Dr 1, Singapore 117411, Singapore
关键词
TUMOR-SUPPRESSOR PATHWAY; CELL CONTACT INHIBITION; ORGAN SIZE CONTROL; ACETYLCHOLINE-RECEPTORS; MYOSIN-II; GROWTH; ADHESION; YAP/TAZ; PHOSPHORYLATION; PROLIFERATION;
D O I
10.1016/j.celrep.2017.02.041
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2464 / 2479
页数:16
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