c-Abl phosphorylation of Delta Np63 alpha is critical for cell viability

The p53 family member p63 has been shown to be critical for growth, proliferation and chemosensitivity. Here we demonstrate that the c-Abl tyrosine kinase phosphorylates the widely expressed Delta Np63 alpha isoform and identify multiple sites by mass spectrometry in vitro and in vivo. Phopshorylation by c-Abl results in greater protein stability of both ectopically expressed and endogenous Delta Np63 alpha. c-Abl phosphorylation of Delta Np63 alpha induces its binding to Yes-associated protein (YAP) and silencing of YAP by siRNA reduces the c-Abl-induced increase of Delta Np63 alpha levels. We further show that cisplatin induces c-Abl phosphorylation of Delta Np63 alpha and its binding to YAP. Overexpression of Delta Np63 alpha, but not the c-Abl phosphosites mutant, protects cells from cisplatin treatment. Finally, we demonstrate the rescue of p63 siRNA-mediated loss of viability with p63siRNA insensitive construct of Delta Np63 alpha but not the phosphosites mutant. These results demonstrate that c-Abl phosphorylation of Delta Np63 alpha regulates its protein stability, by inducing binding of YAP, and is critical for cell viability. Cell Death and Disease (2010) 1, e16; doi:10.1038/cddis.2009.15; published online 21 January 2010