The influence of 2-O sulfated chondroitin and dermatan sulfate in cell response to FGF stimulation

Glycosaminoglycans (GAG) are linear polysaccharide chains composed of repeating disaccharide units. Chondroitin sulfate (CS) and dermatan sulfate (DS) contain of N-acetylgalactosamine (GalNAc) and glucuronic acid/iduronic acid (GlcA/IdoA). The disaccharide units can be modified by sulfate groups at position 4 and 6 of the GalNAc or position 2 of IdoA/GlcA intruding a micro-heterogeneity along CS/DS. CS/DS hybrid chains have important role in various biological processes, because of the binding capacity of proteins such as fibroblast growth factors (FGF), chemokines, and cytokines. The binding and activation of the FGFs is dependent on the structure of the CS/DS and the presence of different sulfation motifs. To 2-O sulfation is a rare sulfation in CS/DS and to study the impact of that modification on FGF signaling we over-express uronyl-2-sulfotransferase (UST). Modulation of the Ust expression lead to changes in cell surface 2-O sulfation and this allows to study FGF signaling events leading to proliferation and migraiton..

Current advances

Nikolovska/Seidler investigate the role of 2-O sulfation of CD/DS in FGF signaling. She was able to show for the first time that overexpression of a sulfotransferase leads to an increase in 2-O sulfated CS/DS followed by increased cell proliferation. To confirm the results, she used LC-ESI-MS for the disaacharide analysis (col. Hensel). The impact of 2-O sulfation on protein expression is analysed by mass spectrometry (col. Siva Kumar). CS/DS are co-receptors for FGFs and binding assays with alkaline phosphatase tagged FGFs (col. Grobe) showed that they bind to similar extent to isolated CS/DS. However, the binding to intact cells was higher if 2-O sulfation was increased. Interestingly, FGF2 treatment did not induce proliferation and Erk signaling in the presence of 2-O sulfation but led to increased migration compared to control cells. The presence of distinctly sulfated CS/DS can modify the mitogenic effect of FGFs triggering the cells towards proliferation or migration. To proof the role of 2-O sulfation in FGF signaling in cells, a proteomic approach using mass spectrometry is used (col. Siva Kumar). Furthermore, the influence 2-O sulfation on migration will be analyzed in melanoma cells, by down-regulating the expression of the enzyme.

Last update 18.06.2013

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