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  current news   Press   selected story    
     
  10 March 2017  
 
Agrin as a mechanotransduction signal regulating YAP through the Hippo pathway
 
 




Authors
Sayan Chakraborty1*, Kizito Njah1, Ajaybabu V. Pobbati1, Ying Bena Lim2, Anandhkumar Raju1, Manikandan Lakshmanan1, Vinay Tergaonkar1, Chwee Teck Lim2,3,4 and Wanjin Hong1,5*

1  Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61    Biopolis drive, Proteos, Singapore 138673.
2  Infectious Diseases Interdisciplinary Research, Singapore-MIT alliance for Research and Technology, 1    CREATE Way, Singapore 138602.
3
  Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3,     Singapore 117583. 
4  Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Singapore 117411.

*Correspondence:
Sayan Chakraborty, PhD
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A-STAR), 61 Biopolis drive, Proteos, Singapore 138673
Phone (+65)65869601
Email: sayanc@imcb.a-star.edu.sg 

Wanjin Hong, PhD,
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A-STAR), 61 Biopolis drive, Proteos, Singapore 138673
Phone (+65)65869606; Fax: (+65) 6779 1117
Email: mcbhwj@imcb.a-star.edu.sg
5  Lead contact ( Wanjin Hong)

Published in Cell Reports (Cell Press) on 7 March 2017.

Please Click the following link to view the full paper:
http://www.cell.com.ejproxy.a-star.edu.sg/cell-reports/pdfExtended/S2211-1247(17)30239-5

Abstract
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 or the precise communicative pathway(s) 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 mechano-activity of YAP through the integrin-focal adhesions and Lrp4/MuSK receptor-mediated signaling pathways. Agrin antagonizes the focal adhesion assembly of the core Hippo components by facilitating ILK-PAK1 signaling and negate the function(s) of Merlin and LATS1/2. We further show that Agrin promotes oncogenesis through YAP-dependent transcription and is clinically relevant in human liver cancer. Together, we propose that Agrin acts as a mechanotransduction signal in the ECM.

Figure

Figure legend

Model depicting the Agrin mediated mechanotransduction pathway regulating YAP. Briefly, liver cancer cells under the influence of stiff ECM have increased Agrin levels that in turn provide enhanced cellular rigidity and stiffness. This mechanical signal is then relayed through Lrp4/MuSK and integrin associated signaling cascade through active focal adhesions that sustain nuclear YAP levels and its target gene(s) expression. Moreover in stiff ECM environment, Agrin activates FAK-ILK-PAK signaling that phosphorylate Merlin at Ser518 residue and inactivates LATS1/2, thereby shutting ‘off’ the Hippo pathway in merlin expressing cells. In addition, Agrin remains capable of sustaining mechanoresponsiveness of YAP through RhoA and actin modulation, specifically in cancer cells lacking functional Merlin or other Hippo components. The maintenance of nuclear YAP through these mechanotransduction pathway(s) is a key event for Agrin mediated oncogenesis.

For more information on WanJin HONG's lab, please click here.