Proteolytic and non-proteolytic roles of membrane type-1 matrix metalloproteinase in malignancy

Abstract

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.

Fig. 1

MMP family. The structure of MMPs is made up of the following domains: 1) a signal peptide; directs MMPs to the secretory or plasma membrane insertion pathway; 2) a prodomain; confers latency to MMPs, 3) a catalytic domain with the active site zinc atom; 4) a hemopexin-like domain; in coordination with the catalytic domain controls the interactions with substrates, 5) a flexible hinge region; links the catalytic and the hemopexin domain and provides each domain mobility relative to the other. The membrane-type MMPs contain an additional transmembrane domain and a short cytoplasmic tail domain (MT1-MMP/MMP-14, MMP-15, MMP-16 and MMP-24) or a glycosylphosphatidyl inositol linkage (MMP-17 and MMP-25) to be tethered to the cell surface. MMP-2 and MMP-9 contain fibronectin-like type II repeats which assist in collagen substrate binding. A hemopexin domain is absent in MMP-7 and MMP-26. MT-MMPs (in addition to several other MMPs) exhibit the RXKR motif in the C-terminal region of the inhibitory prodomain and, therefore, are activated by furin.

Fig. 2

Modular domain structure of furin and six related proprotein-convertases (PCs). The A and B isoforms of PC5/6 are encoded by the same gene. The structure includes (1) the N-terminal signal peptide, which directs proteins into the secretory pathway, (2) a pro-domain, which maintains the inactive zymogen state of PCs and which also acts as an intramolecular chaperone for proper folding, (3) a catalytic domain with the active site that exhibits an Asp-His-Ser catalytic triad and an additional Asn, (4) a barrel-like structured P domain that regulates enzyme stability, (5) a C-terminal domain that contains membrane attachment sequences, a Cys-rich region and intracellular sorting signals.