Publication date: 25th July 2016
Tissue rigidity plays a critical role during development, cancer and wound healing. Cells sense the rigidity of the extracellular matrix (ECM) through a dynamic molecular clutch which applies forces to the ECM, and then transduces them into biochemical signals leading to transcriptional regulation in the nucleus. One such transcriptional regulator is yes associated-protein (YAP), which regulates organ development and homeostasis in health and disease by controlling cell death, proliferation and differentiation. YAP is mechanosensitive since it translocates to the nucleus above a certain extracellular matrix rigidity, but the mechanism involved remains unknown. Here we show that YAP translocation in response to mechanical signals is directly triggered by mechanical force application to the nucleus. We demonstrate that the nucleus is mechanically connected to the ECM only in cells plated on stiff matrices, and that this connection triggers YAP nuclear entry. Further, force transmission to the nucleus is sufficient for YAP translocation independently of focal adhesions, the actin cytoskeleton, and YAP phosphorylation. Our results demonstrate a robust and reversible mechanosensitive mechanism directly mediated by the nucleus, where cell-ECM adhesions serve merely as a force relay checkpoint.
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