Expression and function of matrix metalloproteinase (MMP)-28.
Matrix metalloproteinase-28 (MMP-28, epilysin) is highly expressed in the skin by keratinocytes, the developing and regenerating nervous system and a number of other normal human tissues. In epithelial cells, over-expression of MMP-28 mediates irreversible epithelial to mesenchymal transition concomitant with loss of E-cadherin from the cell surface and an increase in active transforming growth factor beta. We recently reported the expression of MMP-28 in both cartilage and synovium where expression is increased in patients with osteoarthritis. In human chondrosarcoma cells MMP-28 was activated by proprotein convertases and the active form of the enzyme preferentially associated with the extracellular matrix in a C-terminal independent manner. over-expression of MMP-28 in chondrosarcoma cells led to altered cell morphology with increased organisation of actin. Adhesion to type II collagen and fibronectin was increased, and migration across the former was decreased. MMP-28 was localised to the cell surface, at least transiently, in a C-terminal dependent manner. Heparin prevented both extracellular matrix association and cell surface binding of MMP-28 suggesting that both are via heparan sulphate proteoglycans. Over-expression of activatable MMP-28, but not catalytically inactive EA mutant increased the expression and activity of MMP-2, and all forms of MMP-28 tested increased expression of MMP19 and TIMP3 mRNA. These data demonstrate that expression of MMP28 alters cell phenotype towards a more adhesive, less migratory behaviour. Further, MMP-28 activity may reside predominantly in the extracellular matrix, and we are currently searching for substrates in this compartment.
Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, UK.
Ursula R
UR
Rodgers
Lara
L
Kevorkian
Alison K
AK
Surridge
Jasmine G
JG
Waters
Tracey E
TE
Swingler
Kirsty
K
Culley
Sara
S
Illman
Jouko
J
Lohi
Andrew E
AE
Parker
Ian M
IM
Clark
D001859:Bone Neoplasms / Q000201:enzymology*; D002448:Cell Adhesion / Q000502:physiology; D016923:Cell Death; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D002813:Chondrosarcoma / Q000201:enzymology*; D004789:Enzyme Activation; D045683:Furin / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006493:Heparin / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology*; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D011498:Protein Precursors; D019714:Tissue Inhibitor of Metalloproteinases; D006493:Heparin; D045683:Furin; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted