The metastatic spread of tumor cells is usually the cause of death in cancer patients. A more complete understanding of the molecular mechanisms of metastasis is pivotal to finding a cure for any form of malignancy. Gelatinases A and B are directly involved in metastasis. The enzymes play a significant role in the dissolution of the basement membrane and so are critical in the initial stages of invasion and extravasation. The broad long-term objectives of this proposal is twofold. Firstly, to delineate the significance of the binding interactions between gelatinases and the serum glycoproteins, asialofetuin and fetuin on the one hand, and gelatinases and their putative membrane receptors on the other hand. Secondly, to show whether or not membrane bound gelatinases perform other housekeeping roles, apart from the dissolution of the basement membrane.
The specific aims are: a) To elucidate the binding domains in both asialofetuin and gelatinases, b) To evaluate the ability of soluble and immobilized asialofetuin/fetuin and other related proteins in the activation of pro-gelatinases, c) To identify the cell membrane receptors for gelatinases and evaluate the ligand-receptor interactions, d) To analyze the cell surface interactions between gelatinases and the 31 kDa human galactoside binding protein (human galectin-3). Radioactive labeled and cold pro-gelatinases will be incubated with fetuin/asialofetuin and binding, cleavage, and activation of the zymogens monitored. The plasma membrane receptors will also be isolated, purified and the ligand-receptor interactions analyzed. Such studies will provide vital information on the activity of gelatinases on the cell surface as well as in the intracellular spaces.
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