We have purified and determined the complete primary structure of human stromelysin, a secreted metalloprotease with a wide range of substrate specificities. Human stromelysin is synthesized in a preproenzyme form with a calculated size of 53,977 Da and a 17-amino acid long signal peptide. Prostromelysin is secreted in two forms, with apparent molecular masses on NaDodSO4/PAGE of 60 and 57 kDa. The minor 60-kDa polypeptide is a glycosylated form of the major 57-kDa protein containing N-linked complex oligosaccharides. Zymogen activation by trypsin results in the removal of 84 amino acids from the amino terminus of the enzyme generating a 45-kDa active enzyme species. Human stromelysin is capable of degrading proteoglycan, fibronectin, lamiiin, and type IV collagen but not interstitial type I collagen. The enzyme is not capable of activating purified human fibroblast procollagenase. Analysis of its primary structure shows that stromelysin is in all likelihood the human analog of rat transin, which is an oncogene transformation-induced protease. The pattern of enzyme expression in normal and tumorigenic cells revealed that human skin fibroblasts in vitro secrete stromelysin constitutively (1-2 jug per 106 cells per 24 hr). Human fetal lung fibroblasts transformed with simian virus 40, human bronchial epithelial cells transformed with the ras oncogene, fibrosarcoma cells (HT-1080), and a melanoma cell strain (A 2058), do not express this protease nor can the enzyme be induced in these cells by treatment with phorbol 12-myristate 13-acetate. Our data indicate that the expression and the possible involvement of secreted metalloproteases in tumorigenesis result from a specific interaction between the transforming factor and the target cell, which may vary in different species.The extracellular matrix (ECM) of multicellular organisms plays an active role in the formation and maintenance of tissues. The meshwork of ECM macromolecules is deposited by resident cells and provides a substrate for cell adhesion and migration, as well as a permeability barrier in cell-cell communication. A number of processes in normal tissue maintenance [e.g., wound healing (1, 2), bone resorption (3), and uterine involution (4)] as well as certain pathologic processes [for example, rheumatoid arthritis (5, 6), epidermolysis bullosa (7,8), corneal (9, 10) and gingival disease (11)] require connective tissue remodeling, involving a guided degradation of the preexisting ECM. Secreted proteases, required for initiation of degradation of the proteinaceous components of the ECM, also play an important part in processes requiring cell movement, such as tumor invasion and metastasis (12, 13). These enzymes constitute a family of structurally related metalloendoproteases. Previously, we characterized the expression, properties, and primary structure of human fibroblast collagenase (14-16), an enzyme responsible for the initiation of interstitial collagen degradation. In this report, we present the characterization of human fibroblast stromel...