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Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.

ABSTRACT: Alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts occurs in a cell-type-specific manner leading to the mutually exclusive use of exon IIIb in epithelia or exon IIIc in mesenchyme. Epithelial cell-specific exon choice is dependent on (U)GCAUG elements, which have been shown to bind Fox protein family members. In this paper we show that FGFR2 exon choice is regulated by (U)GCAUG elements and Fox protein family members. Fox-2 isoforms are differentially expressed in IIIb+ cells in comparison to IIIc+ cells, and expression of Fox-1 or Fox-2 in the latter led to a striking alteration in FGFR2 splice choice from IIIc to IIIb. This switch was absolutely dependent on the (U)GCAUG elements present in the FGFR2 pre-mRNA and required critical residues in the C-terminal region of Fox-2. Interestingly, Fox-2 expression led to skipping of exon 6 among endogenous Fox-2 transcripts and formation of an inactive Fox-2 isoform, which suggests that Fox-2 can regulate its own activity. Moreover, the repression of exon IIIc in IIIb+ cells was abrogated by interfering RNA-mediated knockdown of Fox-2. We also show that Fox-2 is critical for the FGFR2(IIIb)-to-FGFR2(IIIc) switch observed in T Rex-293 cells grown to overconfluency. Overconfluent T Rex-293 cells show molecular and morphological changes consistent with a mesenchymal-to-epithelial transition. If overconfluent cells are depleted of Fox-2, the switch from IIIc to IIIb is abrogated. The data in this paper place Fox-2 among critical regulators of gene expression during mesenchymal-epithelial transitions and demonstrate that this action of Fox-2 is mediated by mechanisms distinct from those described for other cases of Fox activity.

SUBMITTER: Baraniak AP

PROVIDER: S-EPMC1367178 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.

Baraniak Andrew P AP Chen Jing R JR Garcia-Blanco Mariano A MA

Molecular and cellular biology 20060201 4

Alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts occurs in a cell-type-specific manner leading to the mutually exclusive use of exon IIIb in epithelia or exon IIIc in mesenchyme. Epithelial cell-specific exon choice is dependent on (U)GCAUG elements, which have been shown to bind Fox protein family members. In this paper we show that FGFR2 exon choice is regulated by (U)GCAUG elements and Fox protein family members. Fox-2 isoforms are differentially expressed in II ...[more]

PMID: 16449636

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Project description:Rickettsial infections continue to cause serious morbidity and mortality in severe human cases around the world. Host cell adhesion and invasion is an essential requisite for intracellular growth, replication, and subsequent dissemination of pathogenic rickettsiae. Heparan sulfate proteoglycans [HSPGs] facilitate the interactions between fibroblast growth factor(s) and their tyrosine kinase receptors resulting in receptor dimerization/activation and have been implicated in bacterial adhesion to target host cells. In the present study, we have investigated the contributions of fibroblast growth factor receptors [FGFRs] in rickettsial entry into the host cells. Inhibition of HSPGs by heparinase and FGFRs by AZD4547 (a selective small-molecule inhibitor) results in significant reduction in rickettsial internalization into cultured human microvascular endothelial cells (ECs), which represent the primary targets of pathogenic rickettsiae during human infections. Administration of AZD4547 during R. conorii infection in a murine model of endothelial-target spotted fever rickettsiosis also diminishes pulmonary rickettsial burden in comparison to mock-treated controls. Silencing of FGFR1 expression using a small interfering RNA also leads to similar inhibition of R. rickettsii invasion into ECs. Consistent with these findings, R. rickettsii infection of ECs also results in phosphorylation of tyrosine 653/654, suggesting activation of FGFR1. Using isobaric tag for relative and absolute quantitation [iTRAQ]-based proteomics approach, we further demonstrate association of ?-peptide of rickettsial outer membrane protein OmpA with FGFR1. Mechanistically, FGFR1 binds to caveolin-1 and mediates bacterial entry via caveolin-1 dependent endocytosis. Together, these results identify host cell FGFR1 and rickettsial OmpA as another novel receptor-ligand pair contributing to the internalization of pathogenic rickettsiae into host endothelial cells and the potential application of FGFR-inhibitor drugs as adjunct therapeutics against spotted fever rickettsioses.

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Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.

Publications

Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.

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