Mechanical YAPping

Science Signaling  14 Jun 2011:
Vol. 4, Issue 177, pp. ec162
DOI: 10.1126/scisignal.4177ec162

The mechanical properties of the extracellular matrix (ECM) are integral to the behavior and function of the overlying cells and to the development and tissue architecture of an organism. Indeed, alterations in ECM stiffness or a cell’s perception of such stiffness can lead to pathological conditions. In addition to remodeling of the cytoskeleton, mechanoresponses involve changes in gene activation. By performing a bioinformatic analysis of the differential expression of genes in cultured mammary epithelial cells (MECs) exposed to ECMs of varying stiffness, Dupont et al. discovered an association between genes regulated by enhanced stiffness and gene signatures characteristic of the transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), which have been implicated in signaling by the Hippo pathway. Real-time reverse transcription polymerase chain reaction analysis demonstrated the expression of two YAP- and TAZ-regulated genes, CTGF and ANKRD1, in human MECs grown on stiff hydrogels, whereas the activity of YAP and TAZ in MECs grown on soft matrices was comparable to that in cells treated with YAP- and TAZ-specific short interfering RNAs. Immunofluorescence analysis revealed that YAP and TAZ were localized in the nucleus in MECs grown on hard matrices, whereas both proteins were predominantly cytoplasmic in cells grown on softer ECMs. Cell spreading was sufficient to induce the nuclear localization of YAP and TAZ, but cell-to-cell contact was not required. Moreover, activation of the small guanosine triphosphatase Rho by cell spreading and the resulting tension of the actin cytoskeleton (through the formation of stress fibers) were required for the localization and retention of YAP and TAZ in the nucleus and for their transcriptional activity; these responses were unaffected by depletion of the Hippo signaling component LATS. Depletion of YAP and TAZ prevented the osteogenic differentiation that occurs when mesenchymal stem cells (MSCs) are grown on a stiff ECM. Conversely, YAP- and TAZ-depleted MSCs grown on stiff ECM underwent adipogenic differentiation, a cell fate that normally occurs only in cells grown on a soft matrix. Together, these data suggest that YAP and TAZ act as sensors and mediators of mechanical signals from the environment and may play a role in cell fate determination by the ECM.

S. Dupont, L. Morsut, M. Aragona, E. Enzo, S. Giulitti, M. Cordenonsi, F. Zanconato, J. Le Digabel, M. Forcato, S. Bicciato, N. Elvassore, S. Piccolo, Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). [PubMed]