Fig. 1

Significant alternative splicing changes occurring during EMT. a Key transcription factors upregulated during EMT; gradient color represents their expression increase from epithelial to mesenchymal phenotype. b Schematic representation of EMT progression. From left to right: (i) polarized epithelial cell with strong cell-cell junctions. Par complex and actin filaments localize to the junctions; (ii) epithelial cell with residual junctions starts to re-organize its cytoskeleton and change its morphology. E-cadherin disappears from cell membrane (small yellow square). The Par complex is disassembled and PAR6/aPKC move to the apical cell surface; (iii) the epithelial cell loses its epithelial features and begins to acquire an elongated and spindle-like morphology, while PAR6/aPKC, with other polarity complexes (not shown), allow the establishment of a front-rear polarity. Metalloproteases are secreted in order to degrade the ECM; (iv) a motile mesenchymal cell is able to invade the surrounding tissues. c Expression gradients of key splicing factors regulated during EMT. d Center. AS of genes involved in different EMT programs, including migration and invasion (FGFR2, RON and CD44), polarity and cytoskeleton organization (NUMB, RAC and p120) and transcription regulation (TCFL2). Alternative exons are represented in red, mutually exclusive exon in blue. Left. Scheme of epithelial-specific AS variants. Alternative exons and the encoded amino acids are indicated in red. Right. Mesenchymal-specific isoforms are also shown. Differences in functional properties of epithelial versus mesenchymal isoforms are highlighted: FGFR2 exons IIIb and IIIc confer different ligand binding specificity; ΔRON and Rac1b are constitutively active cytoplasmic isoforms; inclusion of exon 6 in NUMB allows it to interact with Par complex and E-cadherin; p120 isoforms 1-2 localize to AJ, whereas p120 isofoms 3-4 localize with the activate RAC and repress RHOA signaling thus promoting re-organization of the actin cytoskeleton; skipping of exon 4 in TCFL2 generates the more active transcriptional factor TCFL2-Δ4