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.
Rodgers
Ursula R
UR
Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, UK.
Kevorkian
Lara
L
Surridge
Alison K
AK
Waters
Jasmine G
JG
Swingler
Tracey E
TE
Culley
Kirsty
K
Illman
Sara
S
Lohi
Jouko
J
Parker
Andrew E
AE
Clark
Ian M
IM
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