Fig. 2

Alternative splicing in genes with important role in angiogenesis. a) Schematic representation of VEGF-A alternative splicing isoforms. VEGF-A gene with constitutive (green) and alternative (other colours) exons is shown. Thin black lines=introns. PSS: proximal splice site; DSS: distal splice site. Depending on the recognition of different 3' splice sites (PSS or DSS) in exon 8, two classes of VEGF-A isoforms with opposite role in angiogenesis − “pro-angiogenic” (VEGF-Axxxa) or “anti-angiogenic” (VEGF-Axxxb) − are generated. In addition, inclusion/exclusion of alternative exons 6 and 7 give rise to isoforms with different length and heparin affinity. b) Other examples of genes regulated by AS with role in angiogenesis. From the left: (i) L1CAM: skipping of the exon encoding for TM domain (grey cylinder) generates a soluble isoform (L1-ΔTM) with pro-angiogenic functions; (ii) soluble NRP1 isoforms (sNRP1: s₁₁NRP1, s₁₂NRP1, s_IIINRP1, s_IVNRP1) that lack the TM domain and the cytoplasmic tail (grey and orange cylinders) act as decoy receptors for NRP1 ligands and show “anti-angiogenic” properties; (iii) whereas the VASH1A isoform is able to promote vessels normalization, the VASH1B protein (with a diverse C-terminal region involved in heparin binding), has an “anti-angiogenic” activity; (iv) mutually exclusive usage of exon 8 or 9 in FGFR1-3 pre-mRNAs gives rise to distinct isoforms (IIIb and IIIc) that differ for the last portion of the immunoglobulin-like domain 3 (IgIII, indicated with red or blue cylinders) and their ligand specificity; (v) Short endoglin (S-endoglin) has a short cytoplasmic tail (red circle) compared to the long (L-endoglin) isoform. As result S-endoglin and L-endoglin shown a different ability to interact with the TGFβ type I receptor ALK5. Small arrow= low interaction; Big arrow= strong interaction. The different protein domains are indicated by coloured geometric forms. TM = transmembrane domain