Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urokinase (u-PA) proteolytically cleaves both human plasma (pFn) and cellular (cFn) dimeric fibronectin (M(r) 440,000) into four major polypeptides of approximately M(r) 210,000, 200,000, 25,000, and 6,000. Amino acid sequence analysis of the polypeptide fragments indicated that the enzymatic cleavage of Fn occurs at two sites: 1) between an arginine/alanine peptide bond located C-terminal to residue 259; this cleavage liberates the N-terminal M(r) 25,000 fragment and the M(r) 210,000 and M(r) 200,000 polypeptides derived from the A and B chains of Fn, respectively; and 2) between an arginine/threonine peptide bond located C-terminal to residue 2,299, thereby yielding an M(r) 6,000 dimeric fragment containing the C-terminal interchain disulfide bonds. Predigestion of Fn with u-PA increased the molecule's vulnerability to further attack by the enzymes plasmin and cathepsin D. These data provide further biochemical evidence for the proteolytic cleavage of fibronectin by plasminogen activators and substantiate that u-PA digestion of Fn may be an initial event in the local degradation of the extracellular matrix by malignant cells, possessing elevated levels of these enzymes.
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PMID:Localization of the cleavage sites on fibronectin following digestion by urokinase. 146 74

Epithelial ovarian cancer cells spread by two major pathways. One is by exfoliation of tumor cells from the ovarian surface, with resulting implants on peritoneal surfaces such as omentum, diaphragm, and bowel serosa. The second pathway of spread of epithelial ovarian cancer is that of invasion into lymphatic channels, with involvement of the retroperitoneal lymph nodes. Invasion of tumor cells appears to result from a deregulation of the normal processes that govern physiologic controlled invasion. An example of physiologic invasion is that of trophoblastic implantation of the endometrium followed by invasion to access the maternal blood supply in the uterus. The normal invasive process is controled by a balance between protease activity and that of their inhibitors at the level of the individual cell. For the large majority of tumors, extracellular matrix degrading proteases have been shown to have an important role in tumor invasion and metastases. In epithelial ovarian cancer, the major focus has been on the activities of the serine protease urokinase plasminogen activator (uPA) (1-4), and the matrix metalloproteinases (MMP) (5,6). The cysteine proteases, such as cathepsin B, and aspartic proteases, such as cathepsin D, also play a role in invasive-ness of ovarian cancer cells. Each class of proteases contributes to the process of invasion, and cooperates with each other to further the optimal degradation of the extracellular matrix by ovarian cancer cells (7). Urokinase activates plasminogen to plasmin, which activates both pro-uPA and latent MMPs, and cleaves the MMP inhibitor TIMP-2. Moreover, cathepsin B, which is expressed by ovarian cancer cells, appears to facilitate the action of uPA, most likely by activating pro-uPA (8).
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PMID:In vitro invasion assays. 2134 Jul 70