Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway

• Published in: Cell reports (Cambridge) 2017-03, Vol.18 (10), p.2464-2479
• Main Authors: Chakraborty, Sayan, Njah, Kizito, Pobbati, Ajaybabu V., Lim, Ying Bena, Raju, Anandhkumar, Lakshmanan, Manikandan, Tergaonkar, Vinay, Lim, Chwee Teck, Hong, Wanjin
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; Agrin; Agrin - metabolism; Animals; Carcinogenesis; Cell Line; Cell Line, Tumor; Cytoskeleton - metabolism; extracellular matrix; Extracellular Matrix - metabolism; Female; Focal Adhesion Protein-Tyrosine Kinases - metabolism; focal adhesions; Focal Adhesions - metabolism; hippo pathway; Humans; integrins; liver cancer; mechanotransduction; Mechanotransduction, Cellular; Mice, Nude; Phosphoproteins - metabolism; Protein Binding; Protein Stability; Signal Transduction; Transcription Factors; YAP/TAZ
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.041

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. [Display omitted] •Agrin mechanoactivates YAP by negating the Hippo pathway•Agrin transduces matrix rigidity signals to YAP through an integrin-Lrp4/MuSK pathway•Agrin-induced FAK-ILK-PAK1 restricts focal adhesion enrichment of Hippo signaling•The Agrin-YAP mechanotransduction network cooperates in liver cancer development Chakraborty et al. report that the extracellular matrix protein Agrin is a mechanotransducing signal activating YAP through the integrin-focal adhesion-Lrp4/MuSK receptor pathway. Agrin signals matrix and cellular rigidity by activating FAK-ILK-PAK1 signaling that negates the Hippo tumor-suppressor pathway. Importantly, Agrin relies on YAP for oncogenic activities underlying liver cancer.