Go Back MMP 14 (MT1-MMP) prodomain-catalytic domain hemopexin domain

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Matrix metalloproteinases (MMPs) are Zn2+- and Ca2+-dependent endopeptidases which function in the turnover of extracellular matrix components [3]. Presently fifteen secreted MMPs and six membrane-type MMPs are known to be expressed in humans. MT1-MMP consists of 559 amino acid residues with a calculated Mr of 63 516 Da [4, 5]. The following domains and sequence regions are distinguished in MT1-MMP: Prodomain (Ser1 - Arg88), catalytic domain (Tyr89 - Gly261), junction between catalytic domain and hemopexin domain (Gly262 - Gly292), hemopexin-like domain (Pro293 - Cys485) and C-terminal sequence (Pro486 - Val559) with transmembrane segment. A soluble form of MT1-MMP without transmembrane segment has been found in culture medium of a breast carcinoma cell line [6]. MT1-MMP is expressed in adult lung, placenta, kidney, ovaries, intestine, prostate and spleen [5]. Increased amounts of the enzyme are found in tumor tissues as lung carcinoma, gastric carcinoma [7], colon, breast, head and neck carcinoma [8].

MT1-MMP is activated by removal of its prodomain. The reaction is catalyzed by furin, a subtilysin-type serine protease, which recognizes a motif of four basic amino acid residues located between prodomain and catalytic domain [9]. MT1-MMP activates progelatinase A (72-kDa type IV procollagenase) [4, 10, 11] and procollagenase-3 [12] by proteolytic cleavage of their prodomains. The ability of MT1-MMP to activate other matrix metalloproteinases provides potential for enhanced pericellular proteolysis in physiological and pathological processes. In particular, activation of progelatinase A by MT1-MMP is considered to contribute to local degradation of extracellular matrix during cell migration and proliferation. MT1-MMP hydrolyzes also fibrillar collagens I, II and III into characteristic ¾ and ¼ fragments [1,13] and it cleaves a number of other proteins of the extracellular matrix, among them fibronectin, vitronectin, laminin-1 and dermatan sulfate proteoglycan [1,9,13]. The activity of MT1-MMP is poorly inhibited by tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), but efficiently inhibited by TIMP-2 and TIMP-3 [11].