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(Received for publication, September 27, 1996, and in revised form, March 26, 1997)
From the Joint Program in Neonatology, Harvard Medical School,
Boston, Massachusetts 02115
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-
Volume 272, Number 23,
Issue of June 6, 1997
pp. 14713-14720
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
, tumor necrosis
factor-
, 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.
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