Proteolytic and non-proteolytic roles of membrane type-1 matrix metalloproteinase in malignancy.
This manuscript provides an overview of the dynamic interactions which play an important role in regulating cancer cell functions. We describe and discuss, primarily, those interactions which involve membrane type-1 matrix metalloproteinase (MT1-MMP), its physiological inhibitor tissue inhibitor of metalloproteinases-2 (TIMP-2), furin-like proprotein convertases and the low density lipoprotein-related protein 1 (LRP1) signaling scavenger receptor. The interaction among these cellular proteins controls the efficiency of the activation of MT1-MMP and the unorthodox intracellular signaling which is generated by the catalytically inert complex of MT1-MMP with TIMP-2 and which plays a potentially important role in the migration of cancer cells. Our in-depth understanding of these cellular mechanisms may provide the key to solving the puzzling TIMP-2 paradox. This unsolved paradox arises from the fact that TIMP-2 is a powerful inhibitor of MMPs including MT1-MMP, but at the same time high levels of TIMP-2 positively correlate with an unfavorable prognosis in cancer patients. Solving the TIMP-2 paradox may lead to solving a similar PAI-1 paradox and produce a clearer understanding of the biochemical mechanisms which control the functionality of the urokinase-type plasminogen activator*urokinase receptor*plasminogen activator inhibitor type-1 (uPAR*uPA*PAI-1) system in cancer.
Strongin
Alex Y
AY
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. strongin@burnham.org
D000818:Animals; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D043484:Proprotein Convertases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D043484:Proprotein Convertases; D053511:Matrix Metalloproteinase 14