The
syndecan family of transmembrane
heparan sulfate proteoglycans is abundant on the surface of all adherent mammalian cells.
Syndecans bind and modify the action of various
growth factors/
cytokines,
proteases/
antiproteases,
cell adhesion molecules, and extracellular matrix components.
Syndecan expression is highly regulated during
wound repair, a process orchestrated by many of these effectors. Each
syndecan ectodomain is shed constitutively by cultured cells, but the mechanism and significance of this shedding are not understood. Therefore, we examined (i) whether physiological agents active during
wound repair influence
syndecan shedding, and (ii) whether
wound fluids contain shed
syndecan ectodomains. Using SVEC4-10 endothelial cells we find that certain
proteases and
growth factors accelerate shedding of the
syndecan-1 and -4 ectodomains.
Protease-accelerated shedding is completely inhibited by serum-containing media.
Thrombin activity is duplicated by the 14-amino
acid thrombin receptor agonist
peptide that directly activates the
thrombin receptor and is not inhibited by serum.
Epidermal growth factor family members accelerate shedding but
FGF-2,
platelet-derived growth factor-AB,
transforming growth factor-beta,
tumor necrosis factor-alpha, and vascular endothelial cell
growth factor 165 do not. Shed ectodomains are soluble, stable in the
conditioned medium, have the same size core
proteins regardless whether shed at a basal rate, or accelerated by
thrombin or
epidermal growth factor-family members and are found in acute human dermal
wound fluids. Thus, shedding is accelerated by activation of at least two distinct receptor classes,
G protein-coupled (
thrombin) and
protein tyrosine kinase (
epidermal growth factor).
Proteases and
growth factors active during
wound repair can accelerate
syndecan shedding from cell surfaces. Regulated shedding of
syndecans suggests physiological roles for the soluble
proteoglycan ectodomains.