Differential signal transduction of alternatively spliced FGFR2 variants expressed in human mammary epithelial cells.
Gene amplification and protein overexpression of fibroblast growth factor receptor 2 (FGFR2) characterize the SUM-52 breast cancer cell line developed in our laboratory. SUM-52 cells express nine distinct alternatively spliced isoforms of FGFR2. Among these isoforms are two otherwise identical FGFR2 variants that express either the C1 or C3 carboxyl terminus. FGFR2-C3 variants are not normally expressed by human mammary epithelial (HME) cells, and we have shown that overexpression of FGFR2-C3 in HME cells results in potent transformation. In particular, FGFR2-C3 expression leads to robust levels of constitutively tyrosine phosphorylated FRS2 in the absence of ligand stimulation. In contrast, overexpressed FGFR2-C1 requires constant stimulation with exogenous keratinocyte growth factor (KGF) to mimic the signaling capability of FGFR2-C3. However, activation of FRS2 that results from KGF-stimulated FGFR2-C1 signaling is transient and is associated with a mobility shift of FRS2 not observed when this signaling molecule is activated by the C3 isoform of FGFR2. Mutation of the only tyrosine phosphorylated site present in the C1 terminus and absent from C3, Tyr769, did not yield a receptor that rivaled the potent signaling of FGFR2-C3. We therefore conclude that aberrant expression of alternatively spliced isoforms of FGFR2 with the C3 carboxyl terminus in the SUM-52 breast cancer cells results in sustained activation of signal transduction leading to transformation.
Moffa
Allison B
AB
Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan, USA.
Ethier
Stephen P
SP
D017398:Alternative Splicing / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D020033:Protein Isoforms; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013912:Threonine / Q000378:metabolism
D020033:Protein Isoforms; D051523:Fibroblast Growth Factor 7; D013912:Threonine; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2