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Alternative Splicing of Fibroblast Growth Factor Receptor IgIII Loops in Cancer

DOI: 10.1155/2012/950508

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Abstract:

Alternative splicing of the IgIII loop of fibroblast growth factor receptors (FGFRs) 1–3 produces b- and c-variants of the receptors with distinctly different biological impact based on their distinct ligand-binding spectrum. Tissue-specific expression of these splice variants regulates interactions in embryonic development, tissue maintenance and repair, and cancer. Alterations in FGFR2 splicing are involved in epithelial mesenchymal transition that produces invasive, metastatic features during tumor progression. Recent research has elucidated regulatory factors that determine the splice choice both on the level of exogenous signaling events and on the RNA-protein interaction level. Moreover, methodology has been developed that will enable the in depth analysis of splicing events during tumorigenesis and provide further insight on the role of FGFR 1–3 IIIb and IIIc in the pathophysiology of various malignancies. This paper aims to summarize expression patterns in various tumor types and outlines possibilities for further analysis and application. 1. Introduction Fibroblast growth factors (FGFs) are a large family of 23 ligands that serve crucial functions in embryonic development as well as in the adult organisms (for review see [1]). They mediate their signals via a small subfamily of 4 tyrosine kinase receptors (FGFR 1–4). This is a small number of receptors for a large group of ligands, but the system gains significant complexity from the formation of heterodimers as well as a high frequency of alternative splicing events [2, 3] that can be grouped in 3 categories. These categories are (1) the deletion of autoinhibitory domains close to the N- or the C-terminus of the proteins which produces more active and frequently oncogenic receptor variants [4, 5], (2) the IIIb and IIIc variants which are produced by alternative exon usage in the ligand-binding domain [2], and (3) soluble variants that come from exclusion of the exon that codes for the transmembrane region [6, 7]. All of these molecules display distinct biological activities. The IIIb and IIIc variations have been described for FGFRs 1–3 and probably have the strongest impact as they alter the ligand-binding portion of the affected FGFR [8]. This review will therefore focus on the IIIb/IIIc splice variants, their biological function, and the regulation of their formation especially in cancer. It will also describe novel methods for in vitro and in vivo monitoring. 2. Structure and Function of FGFRs 2.1. Expression and Splice Variants The FGFR-genes consist of up to 20 exons that together code

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