Tumor-associated trypsinogen-2 (trypsinogen-2) activates procollagenases (MMP-1, -8, -13) and stromelysin-1 (MMP-3) and degrades type I collagen.

Abstract

A critical step in cancer growth and metastasis is the dissolution of the extracellular matrix surrounding the malignant tumor, which leads to tumor cell invasion and dissemination. Type I collagen degradation involves the initial action of collagenolytic matrix metalloproteinases (MMP-1, -8, and -13) activated by MMP-3 (stromelysin-1). The role of interactive matrix serine proteinases (MSPs), including tumor-associated trypsinogens, has been unclear in collagenolysis. Now, we provide evidence that the major isoenzyme of human tumor-associated trypsinogens, trypsin-2, can directly activate three collagenolytic proMMPs as well as proMMP-3. These proMMP activations are inhibited by tumor-associated trypsin inhibitor (TATI). Furthermore, we demonstrate that trypsin-2 efficiently degrades native soluble type I collagen, which can be inhibited by TATI. However, cell culture studies showed that trypsin-2 transfection into the HSC-3 cell line did not result in MMP-1, -3, -8, and -13 activation but affected MMP-3 and -8 production at the protein level. These findings indicate that human trypsin-2 can be regarded as a potent tumor-associated matrix serine protease capable of being the initial activator of the collagenolytic MMP activation network as well as directly attacking type I collagen.

• Authors: Merja Moilanen, Timo Sorsa, Mathias Stenman, Pia Nyberg, Otso Lindy, Jaana Vesterinen, Annukka Paju, Yrjö T Konttinen, Ulf-Håkan Stenman, Tuula Salo
• Journal: Biochemistry (Biochemistry) Vol. 42 Issue 18 Pg. 5414-20 (May 13 2003) ISSN: 0006-2960 [Print] United States
• PMID: 12731883 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• DNA Primers
• Enzyme Precursors
• PRSS2 protein, human
• Trypsin Inhibitor, Kazal Pancreatic
• Trypsinogen
• Serine Endopeptidases
• Trypsin
• Collagenases
• MMP13 protein, human
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 8
• Matrix Metalloproteinase 1

Topics

• Blotting, Western
• Collagen Type I (metabolism)
• Collagenases (metabolism)
• DNA Primers (chemistry)
• Enzyme Activation
• Enzyme Precursors (metabolism)
• Extracellular Matrix (chemistry)
• Humans
• Matrix Metalloproteinase 1 (metabolism)
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 3 (metabolism)
• Matrix Metalloproteinase 8 (metabolism)
• Polymerase Chain Reaction
• Serine Endopeptidases (pharmacology)
• Trypsin (pharmacology)
• Trypsin Inhibitor, Kazal Pancreatic (pharmacology)
• Trypsinogen (pharmacology)
• Tumor Cells, Cultured (drug effects)