Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity - PubMed (original) (raw)

. 1996 Apr 12;271(15):9135-40.

doi: 10.1074/jbc.271.15.9135.

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Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity

D Pei et al. J Biol Chem. 1996.

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Abstract

Membrane-type matrix metalloproteinase-1 (MT-MMP-1) has been proposed to play a critical role in regulating the expression of tissue-invasive phenotypes in normal and neoplastic cells by directly or indirectly mediating the activation of progelatinase A. To begin characterizing MT-MMP-1 structure-function relationships, transmembrane-deletion mutants were constructed, and the processing of the zymogens as well as the enzymic activity of the mature proteinases was analyzed. We now demonstrate that pro-MT-MMP-1 mutants are efficiently processed to active proteinases following post-translational endoproteolysis immediately downstream of an Arg108-Arg-Lys-Arg basic motif by a proprotein convertase-dependent pathway. The secreted form of active MT-MMP-1 not only displays an N terminus identical with that described for the processed wild-type enzyme at Tyr112 (Strongin, A. Y., Collier, I., Bannikov, G., Marmer, B. L., Grants, G. A., and Goldberg, G. I. (1995) J. Biol. Chem. 270, 5331-5338), but also directly mediated progelatinase A activation via a two-step proteolytic cascade indistinguishable from that observed with intact cells. Furthermore, although the only function previously ascribed to MT-MMP-1 is its ability to act as a progelatinase A activator, purified transmembrane deletion mutants also expressed proteolytic activities against a wide range of extracellular matrix molecules. Given recent reports that MT-MMP-1 ectodomains may undergo intercellular transfer in vivo (Okada, A., Bellocq, J.-P., Rouyer, N., Chenard, M.-P., Rio, M.-C., Chambon, P., and Basset, P. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 2730-2734), our data suggest that soluble forms of the proteinase confer recipient cells with the ability to not only process progelatinase A, but also directly degrade extracellular matrix components.

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