Reactome | FGFR2 alternative splicing

FGFR2 alternative splicing

Stable Identifier

R-HSA-6803529

DOI

10.3180/r-hsa-6803529.1

Type

Pathway

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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
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
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
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	RNA	2006