The long-term objective of this research is to define alterations in the extracellular matrix (ECM) interactions that play a role in the development of cancer. Metastasis of epithelial tumors, such as breast carcinomas, occurs when the cells are no longer constrained by the basement membrane that separates them from the underlying stroma. Matrix metalloproteinases (MMPs) are implicated in degradation of the basement membrane during cancer invasion and metastasis. Their activity is controlled, in part, by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). TIMP-3 is the only member of the TIMP family that localizes to the ECM. Based on our studies of TIMP-3 expression in cultured cells and in vivo, we propose the following hypothesis: TIMP-3 is an onco-fetal protein; although it is syn- thesized in some adult tissues, it is predominantly expressed during embryogenesis and is developmentally regulated. Recently, a tertiary structure of TIMP-2 has been solved by NMR. These coordinates have been used to view the TIMP-2 structure using MidasPlus. TIMP-3 is over 60% homologous to TIMP-2. In looking at the TIMP-2 model, MidasPlus has aided us in making projections of TIMP-3's structure. This has given us some insights to possible sites for the inhibitory interactions, cytokine signaling and localization epitopes. The LOOK software package and TIMP-2 coordinates may aid us in making a model of TIMP-3.
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