α3β1 integrin promotes cell survival via multiple interactions between 14-3-3 isoforms and proapoptotic proteins

Laminin-5 and alpha 3 beta 1 integrin promote keratinocyte survival; however, the downstream signaling pathways for laminin-5/alpha 3 beta 1 integrin-mediated cell survival had not been fully established. We report the unexpected finding of multiple interactions between 14-3-3 isoforms and proapoptotic proteins in the survival signaling pathway. Ln5-P4 motif within human laminin-5 alpha 3 chain promotes cell survival and anti-apoptosis by inactivating Bad and YAP. This effect is achieved through the formation of 14-3-3 zeta/p-Bad and 14-3-3 sigma/p-YAP complexes, which is initiated by alpha 3 beta 1 integrin and FAK/PI3K/Akt signaling. These complexes result in cytoplasmic sequestration of Bad and YAP and their subsequent inactivation. An increase in Akt1 activity in cells induces 14-3-3 zeta and sigma,p-Bad, and p-YAP, promoting cell survival, whereas decreasing Akt activity suppresses the same proteins and inhibits cell survival. Suppression of 14-3-3 zeta with RNA-interference inhibits cell viability and promotes apoptosis. These results reveal a new mechanism of cell Survival whereby the formation of 14-3-3 zeta/p-Bad and 14-3-3 sigma/p-YAP complexes is initiated by laminin-5 stimulation via the alpha 3 beta 1 integrin and FAK/PI3K/Akt signaling pathways, thereby resulting in cell survival and anti-apoptosis. (C) 2009 Elsevier Inc. All rights reserved