FGFR2 alternative splicing

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R-HSA-6803529
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Homo sapiens
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Alternative splicing of the FGFR2 nascent mRNA generates an epithelial specific isoform (FGFR2 IIIb) and a mesenchymal specific isoform (FGFR2 IIIc). The inclusion of exon 8 in FGFR2 IIIb or exon 9 in FGFR2 IIIc alters the C-terminal half of the D3 loop of the receptor and is responsible for the different ligand-binding specificities of the two isoforms (reviewed in Eswarakumar et al, 2005). In recent years, a number of cis- and trans-acting elements have been identified that regulate the alternative splicing event. Exon IIIb repression is mediated by the presence of weak splice sites flanking the exon, an exonic silencing sequence (ESS) within the IIIb exon and both intronic silencing sequences (ISS) upstream and downstream (Carstens et al, 2000; Del Gatto and Breathnach, 1995; Del Gatto et al, 1996; Wagner et al 2005; Wagner and Garcia-Blanco, 2001). Binding of hnRNPA1, PTB1, SR family proteins and other factors to these elements represses the IIIb exon and promotes FGFR2 IIIc expression in mesenchymal cells (Del Gatto-Konczak et al, 1999; Carstens et al, 2000; Wagner et al, 2005; Wagner and Garcia-Blanco, 2001; Wagner and Garcia-Blanco, 2002). In epithelial cells, recruitment of epithelial specific factors shifts the splicing events to favour inclusion of exon 8. ESPN1 and ESPN2 are epithelial-specific factors that bind to an ISE/ISS-3 (intronic splicing enhancer/intronic splicing silencer-3) region within intron 8 to promote FGFR2 IIIb-specific splicing (Warzecha et al, 2009). A complex of RBFOX2, hnRNPH1 and hnRNPF also contribute to epithelial-specific splicing by competing for binding to a site that is occupied by the SR proteins ASF/SF2 in mesenchymal cells (Baraniak et al, 2006; Mauger et al, 2008). Other proteins and sequences have also been identified that appear to contribute to the regulated expression of FGFR2b and FGFR2c, but the full details of the alternative splicing event remain to be worked out (Muh et al, 2002; Newman et al, 2006; Del Gatto et al, 2000; Hovhannisyan and Carstens, 2007).

Literature References
PubMed ID Title Journal Year
10982855 An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein

Carstens, RP, Wagner, EJ, Garcia-Blanco, MA

Mol. Cell. Biol. 2000
9858549 hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer

Del Gatto-Konczak, F, Olive, M, Gesnel, MC, Breathnach, R

Mol. Cell. Biol. 1999
18573884 hnRNP H and hnRNP F complex with Fox2 to silence fibroblast growth factor receptor 2 exon IIIc

Mauger, DM, Lin, C, Garcia-Blanco, MA

Mol. Cell. Biol. 2008
16449636 Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice

Baraniak, AP, Chen, JR, Garcia-Blanco, MA

Mol. Cell. Biol. 2006
8668531 The exon sequence TAGG can inhibit splicing

Del Gatto, F, Gesnel, MC, Breathnach, R

Nucleic Acids Res. 1996
12393912 A Non-sequence-specific double-stranded RNA structural element regulates splicing of two mutually exclusive exons of fibroblast growth factor receptor 2 (FGFR2)

Muh, SJ, Hovhannisyan, RH, Carstens, RP

J. Biol. Chem. 2002
15863030 Cellular signaling by fibroblast growth factor receptors

Eswarakumar, VP, Lax, I, Schlessinger, J

Cytokine Growth Factor Rev 2005
10938105 The RNA-binding protein TIA-1 is a novel mammalian splicing regulator acting through intron sequences adjacent to a 5' splice site

Del Gatto-Konczak, F, Bourgeois, CF, Le Guiner, C, Kister, L, Gesnel, MC, Stévenin, J, Breathnach, R

Mol. Cell. Biol. 2000
19285943 ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing

Warzecha, CC, Sato, TK, Nabet, B, Hogenesch, JB, Carstens, RP

Mol. Cell 2009
15684416 Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb

Wagner, EJ, Baraniak, AP, Sessions, OM, Mauger, D, Moskowitz, E, Garcia-Blanco, MA

J. Biol. Chem. 2005
7651400 Exon and intron sequences, respectively, repress and activate splicing of a fibroblast growth factor receptor 2 alternative exon

Del Gatto, F, Breathnach, R

Mol. Cell. Biol. 1995
12419237 RNAi-mediated PTB depletion leads to enhanced exon definition

Wagner, EJ, Garcia-Blanco, MA

Mol. Cell 2002
11313454 Polypyrimidine tract binding protein antagonizes exon definition

Wagner, EJ, Garcia-Blanco, MA

Mol. Cell. Biol. 2001
17959601 Heterogeneous ribonucleoprotein m is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced exons

Hovhannisyan, RH, Carstens, RP

J. Biol. Chem. 2007
16603716 Identification of RNA-binding proteins that regulate FGFR2 splicing through the use of sensitive and specific dual color fluorescence minigene assays

Newman, EA, Muh, SJ, Hovhannisyan, RH, Warzecha, CC, Jones, RB, McKeehan, WL, Carstens, RP

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