ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis

Reduced expression of the p53 family member p63 has been suggested to play a causative role in cancer metastasis. Here, we show that Delta Np63 alpha, the predominant p63 isoform, plays a major role in regulation of cell migration, invasion and cancer metastasis. We identified mitogen-activated protein (MAP) kinase phosphatase 3 (MKP3) as a downstream target of Delta Np63 alpha that is required for mediating these effects. We show that Delta Np63 alpha regulates extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) activity via MKP3 in both cancer and non-transformed cells. We further show that exogenous Delta Np63 alpha inhibits cell invasion and is dependent on MKP3 upregulation for repression. Conversely, endogenous pan-p63 ablation results in increased cell migration and invasion, which can be reverted by reintroducing the Delta Np63 alpha isoform alone, but not by other isoforms. Interestingly, these effects require Erk2, but not Erk1 expression, and can be rescued by enforced MKP3 expression. Moreover, MKP3 expression is reduced in invasive cancers, and reduced p63 expression increases metastatic frequency in vivo. Taken together, these results suggest an important role for Delta Np63 alpha in preventing cancer metastasis by inhibition of Erk2 signaling via MKP3.