Abstract
Endostatin, an inhibitor of angiogenesis and tumor growth, was identified originally in conditioned media of murine hemangioendothelioma (EOMA) cells. N-terminal amino acid sequencing demonstrated that it corresponds to a fragment of basement membrane collagen XVIII. Here we report that cathepsin L is secreted by EOMA cells and is responsible for the generation of endostatin with the predicted N-terminus, while metalloproteases produce larger fragments in a parallel processing pathway. Efficient endostatin generation requires a moderately acidic pH similar to the pericellular milieu of tumors. The secretion of cathepsin L by a tumor cell line of endothelial origin suggests that this cathepsin may play a role in angiogenesis. We propose that cleavage within collagen XVIII's protease-sensitive region evolved to regulate excessive proteolysis in conditions of induced angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cathepsin L
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Cathepsins / metabolism*
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Cell Line
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Collagen / chemistry
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Collagen / metabolism*
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Collagen Type XVIII
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Culture Media, Conditioned / metabolism
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Cysteine Endopeptidases / metabolism
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Endopeptidases*
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Endostatins
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Endothelium, Vascular / cytology
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / metabolism
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Enzyme Precursors / metabolism
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Humans
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Hydrogen-Ion Concentration
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Kinetics
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Matrix Metalloproteinases / metabolism
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Mice
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Models, Biological
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Molecular Weight
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism*
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Protein Processing, Post-Translational*
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Tumor Cells, Cultured
Substances
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Collagen Type XVIII
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Culture Media, Conditioned
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Endostatins
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Enzyme Precursors
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Peptide Fragments
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Recombinant Fusion Proteins
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Collagen
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Cathepsins
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Endopeptidases
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Cysteine Endopeptidases
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CTSL protein, human
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Cathepsin L
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Ctsl protein, mouse
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Matrix Metalloproteinases