Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 receptor binding in breast carcinomas.
Binding of fibroblast growth factors (FGFs) to their tyrosine kinase-signaling receptors (FGFRs) requires heparan sulfate (HS). HS proteoglycans (HSPGs) determine mitogenic responses of breast carcinoma cells to FGF-2 in vitro. For this study, we examined the role of HSPGs as modulators of FGF-2 binding to FGFR-1 in situ and in vitro. During stepwise reconstitution of the FGF-2/HSPG/FGFR-1 complex in situ, we identified an elevated ability of breast carcinoma cell HSPGs to promote receptor complex formation compared to normal breast epithelium. HSPGs isolated from the MCF-7 breast-carcinoma cell line were then fractionated according to their ability to assemble the FGF-2 receptor complex. All MCF-7 HSPGs are decorated with HS chains similarly capable of promoting FGF-2 receptor complex formation. In this in vitro model, syndecan-1 and syndecan-4 are the cell surface HSPGs contributing most to the complex formation. Relative expression levels of these syndecans in human breast carcinoma tissues correlate well with receptor complex formation in situ, indicating that in breast carcinomas, core protein levels determine FGF-2 receptor complex formation. However, variances in syndecan expression levels do not explain the difference in FGF-2 receptor complex formation between normal and malignant epithelial cells, suggesting that alterations in HS structure occur during malignant transformation.
Mundhenke
Christoph
C
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 52792-8550, USA.
Meyer
Kristy
K
Drew
Sally
S
Friedl
Andreas
A
D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D053668:Syndecan-1; D053671:Syndecan-4; D053667:Syndecans; D014018:Tissue Distribution
D019812:Heparan Sulfate Proteoglycans; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; C508241:SDC1 protein, human; C508304:SDC4 protein, human; D053668:Syndecan-1; D053671:Syndecan-4; D053667:Syndecans; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2