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(Received for publication, April 30, 1996, and in revised form, April 9, 1997)
From the Increased production of proteinases, such as
matrix metalloproteinases (MMPs), is a characteristic feature of
malignant tumors. Some human cancers and cell lines derived from them
also express trypsinogen, but the function of the extrapancreatic
trypsin has remained unclear. In this study we cloned and sequenced
trypsinogen-2 cDNA from human COLO 205 colon carcinoma cells and
characterized the ability of the enzyme to activate latent human type
IV procollagenases (proMMP-2 and proMMP-9). As shown by cloning and
N-terminal amino acid sequencing, the amino acid sequence of
tumor-associated trypsin-2 is identical to that of pancreatic
trypsin-2. We found that both pancreatic trypsin-2 and tumor
cell-derived trypsin-2 are efficient activators of proMMP-9 and are
capable of activating proMMP-9 at a molar ratio of 1:1000, the
lowest reported so far. Human trypsin-2 was a more efficient
activator than widely used bovine trypsin and converted the 92-kDa
proMMP-9 to a single 77-kDa product that was not fragmented further.
The single peptide bond cleaved by trypsin-2 in proMMP-9 was
Arg87-Phe88. The generation of the 77-kDa
species coincided with the increase in specific activity of MMP-9. In
contrast, trypsin-2 only partially activated proMMP-2. Trypsin-2
cleaved the Arg99-Lys100 peptide bond of
proMMP-2 generating 62-65-kDa MMP-2 species. Trypsin-2-induced
proMMP-2 and -9 conversions were inhibited by tumor-associated trypsin
inhibitor added either prior to or during activation indicating that
proMMPs were not activated autocatalytically. Trypsin-2 also activated
proMMPs associated with tissue inhibitor of matrix metalloproteinases,
the complexes of which are thought to be the major MMP forms in
vivo. The ability of human tumor cell-derived trypsin-2 to
activate latent MMPs suggests a role for trypsin-2 in
initiating the proteinase cascade that mediates tumor invasion and
metastasis formation.
Volume 272, Number 34,
Issue of August 22, 1997
pp. 21067-21074
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
,
,
, Departments of Medical Chemistry and
Periodontology, the || Department of Clinical Chemistry, and
the Division of Biochemistry, University of Helsinki, FIN-00014
Helsinki, Finland, the ¶ Departments of Oral Surgery and Pathology
and the Department of Biochemistry and
Biocenter, University of Oulu, Oulu, FIN-99020 Finland, the
** Department of Anatomy and IVth Department of Medicine and the
§§ Departments of Oral Surgery and Surgery,
University of Helsinki and Helsinki University Central Hospital,
Helsinki, Finland, and the ¶¶ Department of Biochemistry,
University of Bielefeld, Bielefeld,
Postfach 100131, 33501 Bielefeld, Germany
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