YAP1 mediates anoikis through failed integrin adhesion reinforcement

Mechanical signals from the extracellular matrix (ECM) can determine cell fates, but distinct cells can respond to the same signal differently. In particular, ECM rigidity can drive a binary life/death cell decision, but how such decisions are made is not clear. We find that it is not the rigidity of the ECM per se, but rather the balance between the forces generated by cells and the resistance that the ECM provides which determines cell fate. Slight reduction of the contraction forces of rigidity-dependent cells leads to assembly of mature focal adhesions and survival of the cells on a soft ECM. Accordingly, elevation of cellular contractions leads to FA disassembly and increased cell death on a stiff ECM. Moreover, our studies show that Yes-Associated Protein 1 (YAP1) is recruited and phosphorylated at the Y357 site in nascent adhesions, but not in mature ones, and that the accumulation of pY357-YAP due to failure of adhesion maturation triggers a YAP-dependent apoptotic pathway. These results thus provide a direct link between mechanosensing and anoikis and show that the cellular decisions can be switched based on the cell-matrix force balance. Given the known role of YAP1 in mediating pro-proliferation signals, these results place YAP1 as key molecule in the binary decision to grow or apoptose based on signals from the ECM.