In addition to diseases, many other different conditions, such as cell or tissue type, signaling, and developmental state, have been linked closely to differential splicing, instating the concept of “RNA code” or “splicing code.”
18,27,28 The establishment of RNA code is achieved, for the most part, through the variable expression/interaction of splicing proteins and/or context-specific regulatory factors. Examples of such factors would be the cell type-specific splicing proteins, such as Nova, nPTB, MBNL, and ESRPs.
15,28,29 Epithelial splicing regulatory proteins (ESRP1 and ESRP2) are the first identified epithelial-restricted RNA binding proteins that modulate alternative splicing of a number of epithelial-type transcripts, including FGFR2, ENAH, CTNND1, and CD44.
29,30 Exons that are regulated by ESRPs displayed high level of correlation with epithelial-to-mesenchymal transition (EMT), which leads to loss of cell adhesion, altered cell morphology, and acquisition of cellular motility/invasiveness.
31–33 These observations are of our particular interest because, as mentioned earlier, many previous studies on PNN have revealed consistently PNN's specific impact on epithelial cell adhesion and motility,
2,4,5,34 as well as its involvement in pre-mRNA splicing.
6,7,9,10,35 Thus, considering their similar impact on epithelial phenotypes and alternative splicing, we hypothesize that PNN may function as a component of splicing network in epithelial cells through the functional connection with epithelial-specific splicing factors, such as ESRP proteins.