Mast cell-dependent activation of pro matrix metalloprotease 2: A role for serglycin proteoglycan-dependent mast cell proteases.
The formation of active matrix metalloprotease-2 (MMP-2) requires the proteolytic processing of proMMP-2, a process that can occur through the formation of a ternary complex between proMMP-2, the tissue inhibitor of metalloprotease-2 and membrane type 1-MMP. However, other activation mechanisms have been suggested, and in this study we investigated whether mast cells (MCs) may play a role in the activation of proMMP-2. Murine peritoneal cells, a mixture of macrophages, lymphocytes and MCs, were cultured ex vivo. Addition of proMMP-2 to resting peritoneal cell cultures resulted in only slow conversion of proMMP-2 into the active enzyme. However, when MC degranulation was provoked using a calcium ionophore, proMMP-2 processing was markedly enhanced. When the peritoneal cell populations were depleted in MCs, proMMP-2 processing was abrogated, but was reconstituted when purified MCs were added to the depleted cultures. ProMMP-2 processing was sensitive to serine protease inhibitors, but not to inhibitors of other classes of proteases. Furthermore, proMMP-2 processing was completely abrogated in cells lacking serglycin, a proteoglycan that has previously been shown to mediate storage of a variety of MC serine proteases. Taken together, these results suggest a novel mode of proMMP-2 activation mediated by serglycin-dependent MC serine proteases.
Lundequist
Anders
A
Department of Molecular Biosciences, The Biomedical Center, Swedish University of Agricultural Sciences, P.O. Box 575, S-751 23 Uppsala, Sweden.
Abrink
Magnus
M
Pejler
Gunnar
G
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin; D020778:Matrix Metalloproteinase 2