Matrilysin (matrix metalloprotease-7) cleaves membrane-bound annexin II and enhances binding of tissue-type plasminogen activator to cancer cell surfaces.
Matrilysin (matrix metalloproteinase-7) plays important roles in tumor progression. It was previously found that matrilysin binds to the surface of colon cancer cells to promote their metastatic potential. In this study, we identified annexin II as a novel membrane-bound substrate of matrilysin. Treatment of human colon cancer cell lines with active matrilysin released a 35 k Da annexin II form, which lacked its N-terminal region, into the culture supernatant. The release of the 35 k Da annexin II by matrilysin was significantly enhanced in the presence of serotonin or heparin. Matrilysin hydrolyzed annexin II at the Lys9-Leu10 bond, thus dividing the protein into an N-terminal nonapeptide and the C-terminal 35 k Da fragment. Annexin II is known to serve as a cell surface receptor for tissue-type plasminogen activator (tPA). Although the matrilysin treatment liberated the 35 k Da fragment of annexin II from the cell surface, it significantly increased tPA binding to the cell membrane. A synthetic N-terminal nonapeptide of annexin II bound to tPA more efficiently than intact annexin II. This peptide formed a heterodimer with intact annexin II in test tubes and on cancer cell surfaces. These and other results suggested that the nonapeptide generated by matrilysin treatment might be anchored to the cell membrane, possibly by binding to intact annexin II, and interact with tPA via its C-terminal lysine. It is supposed that the cleavage of cell surface annexin II by matrilysin contributes to tumor invasion and metastasis by enhancing tPA-mediated pericellular proteolysis by cancer cells.
Tsunezumi
Jun
J
Kihara Institute for Biological Research, Yokohama City University, Japan.
Yamamoto
Kazuhiro
K
Higashi
Shouichi
S
Miyazaki
Kaoru
K
D017306:Annexin A2 / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D017306:Annexin A2; D010446:Peptide Fragments; D010959:Tissue Plasminogen Activator; D020783:Matrix Metalloproteinase 7