Syndecan-2 cytoplasmic domain upregulates Matrix Metalloproteinase-7 expression via Protein KinaseC{gamma} mediated FAK/ERK signaling pathway in colon cancer [Signal Transduction]

The syndecan family of heparan sulfate proteoglycans contribute to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that over-expression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) in parallel with upregulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related nonkinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2-mediated upregulation of MMP-7. Activation of protein kinase C (PKC) enhanced syndecan-2-mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKCγ to the membrane. Expression of syndecan-2 harboring a phospho-mimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental supression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2-mediated upregulation of MMP-7 in the early period after syndecan-2 over-expression. Taken together, these findings suggest that syndecan-2's cytoplasmic domain upregulates MMP-7 expression in colon cancer cells via PKCγ-mediated activation of FAK/ERK signaling.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2fMuqY1
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