PKC Regulates YAP Expression through Alternative Splicing of YAP 3′UTR Pre-mRNA by hnRNP F

The Yes-associated protein (YAP) is a transcriptional co-activator that plays critical roles in organ development and tumorigenesis, and is verified to be inhibited by the Hippo signaling pathway. In the present study, we show that the YAP 3 ' UTR is alternatively spliced to generate a novel 950 bp 3 ' UTR mRNA from the full length 3 ' UTR region (3483 bp) in human cancer cells. The ratio of full length 3 ' UTR YAP mRNA to alternatively spliced 3 ' UTR YAP mRNA is up-regulated by exposure of the cells to PKC inhibitor chelerythrine chloride. Further study using luciferase reporter assay showed that the expression of the alternatively spliced 3 ' UTR mRNA is much lower compared with the full length 3 ' UTR mRNA, suggesting that alternatively spliced 3 ' UTR YAP mRNA may have a shorter half-life than full length 3 ' UTR mRNA. Interestingly, PKC represses YAP 3 ' UTR-mediated mRNA stability is dependent on a splicing factor, hnRNP F. Activation of PKC induces nuclear translocation of cytosolic hnRNP F. Ectopic expression of hnRNP F enhances YAP 3 ' UTR splicing. Our results suggest that hnRNP F regulates YAP 3 ' UTR-mediated mRNA stability in an alternative splicing-dependent manner, and PKC regulated YAP expression is dependent on nuclear translocation of hnRNP F in human cancer cell lines.