The role and mechanism of fibroblast growth factor receptor 2 in cellular transformation

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  • March 22, 2019
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  • Cha, Jiyoung
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Our laboratory recently identified fibroblast growth factor receptor 2 (FGFR2) as a transforming gene using a cDNA expression library screen for novel oncogenes expressed in human breast carcinoma cells. An important feature and mode of FGFR2 function is the expression of structural variants of FGFR2 that are encoded by transcripts that arise alternative gene splicing. The tissue-restricted nature of some splice variant transcripts, together with the functional and biological differences of FGFR2 splice variant protein products, provides mechanisms of regulation of receptor function distinct from regulation of expression of receptor ligands. The first major splicing event occurs in the sequences encoding the amino-terminal extracellular domain, involving the third immunoglobulin (Ig-III)-like domain, to generate either the epithelial cell-specific IIIb or mesenchymal cell-specific IIIc isoforms. The second major splicing occurs in sequences that encode the intracellular carboxyl-terminus, resulting in three splice variants that differ in their carboxyl-terminal sequences have been identified (designated C1, C2 and C3). My studies have focused on defining the role of these two major alternative splicing events in FGFR2 function and oncogenesis. First, I found preferential expression of the mesenchymal-specific FGFR2 IIIc splice variant in invasive breast carcinomas. FGFR2 IIIc expression was associated with loss of expression of epithelial cell-specific and the gain of expression of mesenchymal cell-specific markers. These observations suggest that IIIb to IIIc exon switching may be involved in tumor cell invasion and metastasis. Additionally, I evaluated the signaling and transforming activity of the epithelial cell-specific isoform in mammary epithelial cells. Second, I compared the transforming potency of the C1, C2 and C3 splicing variants and found that a hierarchy of transforming activity that correlated with progressive loss of carboxyl terminal sequences. I determined that one mechanism for the enhanced transforming activity of FGFR2 IIIb C3 involves loss of the 770YLDL sorting motif and impaired internalization and a gain of ligand-independent FRS2 activation. Together, my studies provide further evidence for alternative gene splicing as a mechanism for causing aberrant FGFR2 function in promoting human oncogenesis.
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  • In Copyright
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  • Der, Channing
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  • Open access
Date uploaded
  • October 19, 2010

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