Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP.
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, R(89)-R-P-R-C(93) and R(108)-R-K-R-Y(112), 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 R(89)-R-P-R-C(93) 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.
Remacle
A G
AG
The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Rozanov
D V
DV
Fugere
M
M
Day
R
R
Strongin
A Y
AY
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D045683:Furin / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D011499:Protein Processing, Post-Translational; D020133:Reverse Transcriptase Polymerase Chain Reaction
D045683:Furin; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated