Remacle A G, Rozanov D V, Fugere M, Day R, Strongin A Y
The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Oncogene. 2006 Sep 14;25(41):5648-55. doi: 10.1038/sj.onc.1209572. Epub 2006 Apr 24.
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.
促进侵袭的膜型-1基质金属蛋白酶（MT1-MMP）在癌细胞中作为一种癌基因发挥作用，并作为细胞表面蛋白水解事件的介质。为了发挥其功能活性，MT1-MMP需要蛋白酶解去除前结构域序列。在MT1-MMP的前结构域序列中有两个潜在的弗林蛋白酶切割基序，R(89)-R-P-R-C(93)和R(108)-R-K-R-Y(112)。我们的数据表明弗林蛋白酶和相关的前体蛋白转化酶（PCs）在介导MT1-MMP的激活以及癌细胞表面功能性活性MT1-MMP的水平方面发挥重要作用。我们已经确定跨越第一个切割位点的肽序列对弗林蛋白酶和PC5/6敏感，而第二个序列对弗林蛋白酶以及PC5/6、PC7和PACE4敏感。然而，在MT1-MMP酶原的结构中，PCs无法接近R(89)-R-P-R-C(93)位点。我们的研究还证明了MT1-MMP酶原的激活与摄取率以及该酶之间存在直接的功能联系。因此，潜在的MT1-MMP酶原的摄取率明显超过活性酶的摄取率。我们得出结论，弗林蛋白酶和相关的PCs是专门细胞机制的重要组成部分，该机制控制细胞表面功能性活性、成熟的MT1-MMP酶的水平，以持续支持细胞周围蛋白水解的效能。
