Opposite Roles of Tra2 beta and SRSF9 in the v10 Exon Splicing of CD44

CD44 is a transmembrane glycoprotein involved in cell-cell and cell-matrix interactions. Several CD44 protein isoforms are generated in human through alternative splicing regulation of nine variable exons encoding for the extracellular juxta-membrane region. While the CD44 splicing variants have been described to be involved in cancer progression and development, the regulatory mechanism(s) underlying their production remain unclear. Here, we identify Tra2beta and SRSF9 as proteins with opposite roles in regulating CD44 exon v10 splicing. While Tra2beta promotes v10 inclusion, SRSF9 inhibits its inclusion. Mechanistically, we found that both proteins are able to target v10 exon, with GAAGAAG sequence being the binding site for Tra2beta and AAGAC that for SRSF9. Collectively, our data add a novel layer of complexity to the sequential series of events involved in the regulation of CD44 splicing.