Informace o publikaci

Hippo effector yap is a key regulator of cell-matrix interaction


CRUZ Jorge Oliver-De La NARDONE Giorgia VRBSKÝ Jan MELAJOVÁ Katarína MARTINI Cecilia CALUORI Guido PAGLIARI Stefania MARTINO Fabiana STOKIN Gorazd Bernard FORTE Giancarlo

Rok publikování 2017
Druh Článek v odborném periodiku
Časopis / Zdroj ECM Journal
Fakulta / Pracoviště MU

Lékařská fakulta

Obor Genetika a molekulární biologie
Popis The extracellular matrix (ECM) is the non-cellular constituent of the tissues that, far from being an inert structural scaffold, provides biochemical and biomechanical cues that impact on cell behavior. Several reports have focused on the molecular systems by which the ECM interaction impacts on the Hippo signaling pathway to regulate YAP nuclear shuttling and its consequent co-transcriptional activity1,2.In the present work, we describe the mechanism by which the mechanotransducer YAP directly controls through its transcriptional activity both the deposition of extracellular matrix components and the assembly of the inner apparatus of cell-ECM interaction.In fact, by exploiting ChIP-seq technology and YAP mutants obtained by CRISPR/Cas9 targeted approach, we unveil a number of targets of YAP-DNA binding activity that lead to the formation of membrane complexes devoted to the interaction with ECM including various integrin subunits like ITGA1, ITGA4, ITGAVand ITGB1, talin2, cadherins and catenins. At the same time, YAP binds DNA elements connected to the activation of genes encoding for ECM structural proteins like versican, collagens, laminins, fibronectin and osteonectin or involved in the processing of ECM components, like hyaluronan synthase 3, connective tissue growth factor (CTGF) and metallopeptidases.As expected, YAP mutant clones underwent a substantial switch in the expression of genes involved in structural ECM composition and remodeling, thus leading to the complete absence of focal adhesions. As a consequence, cells failed to spread, invade and migrate through the surrounding matrix, when challenged in 2D and 3D assays and lose the ability to spread and acquire the given shape, develop tension through the cytoskeleton and exert force against the surrounding ECM.Consistent with the model of YAP acting as a master of cell-ECM interaction, cell biophysical parameters were partially recovered by the re-expression of ITGAV integrin subunit in conjunction with ITGB3 subunit, two of the proteins being more affected in YAP-defective cells.In conclusion, YAP functions as an important regulator of the cell-matrix interface, being able to control the expression of crucial genes involved in the compositionand arrangement of the extracellular environment, together with key components of cell mechanosome. Moreover, these results pave the way for the design of novel biomaterials controlling cell adhesion and ECM deposition by tuning YAP expression.References:1. D. Mosqueira, S. Pagliari, K. Uto et al. (2014), ACS Nano. 8(3):2033-472 NG. Kim and BM. Gumbiner (2015), J Cell Biol. 210(3): 503–515

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