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  • Original Article
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Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Oncogene volume 25, pages 5648–5655 (2006)Cite this article

Abstract

Invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) functions in cancer cells as an oncogene and as a mediator of proteolytic events on the cell surface. To exert its functional activity, MT1-MMP requires proteolytic removal of the prodomain sequence. There are two potential furin cleavage motifs, R89-R-P-R-C93 and R108-R-K-R-Y112, in the prodomain sequence of MT1-MMP. Our data suggest an important role of furin and related proprotein convertases (PCs) in mediating both the activation of MT1-MMP and the levels of functionally active MT1-MMP at the surface of cancer cells. We have determined that the peptide sequence that spans the first cleavage site is susceptible to furin and PC5/6, whereas the second sequence is susceptible to furin and also to PC5/6, PC7 and PACE4. In the structure of the MT1-MMP proenzyme, the R89-R-P-R-C93 site, however, is inaccessible to PCs. Our studies also demonstrated a direct functional link between the activation and the uptake rate of the proenzyme and the enzyme of MT1-MMP. Thus, the uptake rate of the latent MT1-MMP proenzyme noticeably exceeded that of the active enzyme. We conclude that furin and related PCs are the essential components of the specialized cellular machinery that controls the levels of the functionally active, mature, MT1-MMP enzyme on the cell surface to continually support the potency of pericellular proteolysis.

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Abbreviations

BGN:

benzyl 2-acetamido-2-deoxy-α-D-galactopyranoside

CT:

cytoplasmic tail

dec-RVKR-cmk:

decanoyl-Arg-Val-Lys-Arg-chloromethylketone

HRP:

horseradish peroxidase

MESNA:

2-mercaptoethane sulfonic acid

MT1-MMP:

membrane type-1 matrix metalloproteinase

PA83 and PA63:

anthrax-protective antigen-83 and –63, respectively

PC:

proprotein convertase

PDX:

α1-anti-trypsin Portland; pERTKR-amc, pyro-Glu-Arg-Thr-Lys-Arg-methyl-coumaryl-7-amide

PMSF:

phenylmethylsulfonylfluoride

RT–PCR:

reverse transcription-polymerase chain reaction amplification

WT:

wild-type

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Acknowledgements

This work was supported by NIH Grants CA83017, CA77470 and RR020843 (AYS), and by the Canadian Institutes of Health Research operating grants to RD and a studentship to MF.

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Authors and Affiliations

  1. The Burnham Institute for Medical Research, La Jolla, CA, USA

    A G Remacle, D V Rozanov & A Y Strongin

  2. Department of Pharmacology, Institut de Pharmacologie, Faculte de medecine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada

    M Fugere & R Day

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  1. A G Remacle
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  2. D V Rozanov
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  3. M Fugere
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  4. R Day
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Correspondence to A Y Strongin.

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Remacle, A., Rozanov, D., Fugere, M. et al. Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP. Oncogene 25, 5648–5655 (2006). https://doi.org/10.1038/sj.onc.1209572

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