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.
Graphical Abstract Highlights d Extracellular matrix protein Agrin recruits ECs within tumors d Agrin promotes in vitro and in vivo tumor angiogenesis d Agrin and ECM stiffness stabilize VEGFR2 by Lrp4-Integrin b1-FAK axis d Targeting Agrin inhibits tumor angiogenesis by impairing VEGFR2 levels
Company Disease Tests Technology/biomarkers Biospecimen Status EpiGene Cervical and oral cancers Cervi-M assay Oral-M assay Methylation-specific-qPCR (PAX1 and ZNF582) Human epithelial cells (cell scrapings from cervical brush for cervical cancer and from oral swabs for oral cancer) CE marked Epigenomics Colon and lung cancers Epi proColon Epi proLung MethyLight (SEPT9 for colon; SHOX2 and PTGER4 for lung)
An orchestrated wound healing program drives skin repair via collective epidermal cell proliferation and migration. However, the molecular determinants of the tissue microenvironment supporting wound healing remain poorly understood. Herein we discover that proteoglycan Agrin is enriched within the early wound-microenvironment and is indispensable for efficient healing. Agrin enhances the mechanoperception of keratinocytes by augmenting their stiffness, traction stress and fluidic velocity fields in retaliation to bulk substrate rigidity. Importantly, Agrin overhauls cytoskeletal architecture via enhancing actomyosin cables upon sensing geometric stress and force following an injury. Moreover, we identify Matrix Metalloproteinase-12 (MMP12) as a downstream effector of Agrin’s mechanoperception. We also reveal a promising potential of a recombinant Agrin fragment as a bio-additive material that assimilates optimal mechanobiological and pro-angiogenic parameters by engaging MMP12 in accelerated wound healing. Together, we propose that Agrin-MMP12 pathway integrates a broad range of mechanical stimuli to coordinate a competent skin wound healing niche.
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