title: Agrin as a Mechanotransduction Signal Regulating YAP through the Hippo Pathway.
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 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.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore. Electronic address: sayanc@imcb.a-star.edu.sg.
authors.forename: Sayan
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Kizito
authors.initials: K
authors.lastname: Njah
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Ajaybabu V
authors.initials: AV
authors.lastname: Pobbati
authors.affiliation: Infectious Diseases Interdisciplinary Research, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore 138602, Singapore.
authors.forename: Ying Bena
authors.initials: YB
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Anandhkumar
authors.initials: A
authors.lastname: Raju
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Lakshmanan
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: Infectious Diseases Interdisciplinary Research, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Singapore 138602, Singapore; Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583, Singapore; Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Singapore 117411, Singapore.
authors.forename: Chwee Teck
authors.initials: CT
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore. Electronic address: mcbhwj@imcb.a-star.edu.sg.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018171:Agrin / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis; D002460:Cell Line; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D008819:Mice, Nude; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D018171:Agrin; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Agrin; YAP/TAZ; extracellular matrix; focal adhesions; hippo pathway; integrins; liver cancer; mechanotransduction