Secreted cathepsin L generates endostatin from collagen XVIII.
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.
Felbor
U
U
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Dreier
L
L
Bryant
R A
RA
Ploegh
H L
HL
Olsen
B R
BR
Mothes
W
W
D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D002460:Cell Line; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D043170:Collagen Type XVIII; D017077:Culture Media, Conditioned / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D010450:Endopeptidases; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured
D043170:Collagen Type XVIII; D017077:Culture Media, Conditioned; D043169:Endostatins; D004792:Enzyme Precursors; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D003094:Collagen; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D020782:Matrix Metalloproteinases