Matrilysin (MMP-7) cleaves C-type lectin domain family 3 member A (CLEC3A) on tumor cell surface and modulates its cell adhesion activity.
Matrilysin (MMP-7) plays important roles in tumor progression. Previous studies have suggested that MMP-7 binds to tumor cell surface and promotes their metastatic potential. In this study, we identified C-type lectin domain family 3 member A (CLEC3A) as a membrane-bound substrate of MMP-7. Although this protein is known to be expressed specifically in cartilage, its message was found in normal breast and breast cancer tissues as well as breast and colon cancer cell lines. Because few studies have been done on CLEC3A, we overexpressed its recombinant protein in human cancer cells. CLEC3A was found in the cell membrane, extracellular matrix (ECM), and culture medium of the CLEC3A-expressing cells. CLEC3A has a basic sequence in the NH(2)-terminal domain and showed a strong heparin-binding activity. MMP-7 cleaved the 20-kDa CLEC3A protein, dividing it to a 15-kDa COOH-terminal fragment and an NH(2)-terminal fragment with the basic sequence. The 15-kDa fragment no longer had heparin-binding activity. Treatment of the CLEC3A-expressing cells with MMP-7 released the 15-kDa CLEC3A into the culture supernatant. Furthermore, the 20-kDa CLEC3A promoted cell adhesion to laminin-332 and fibronectin substrates, but this activity was abrogated by the cleavage by MMP-7. These results suggest that CLEC3A binds to heparan sulfate proteoglycans on cell surface, leading to the enhancement of cell adhesion to integrin ligands on ECM. It can be speculated that the cleavage of CLEC3A by MMP-7 weakens the stable adhesion of tumor cells to the matrix and promotes their migration in tumor microenvironments.
Tsunezumi
Jun
J
Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama, Japan.
Higashi
Shouichi
S
Miyazaki
Kaoru
K
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D003110:Colonic Neoplasms / Q000473:pathology*; D005109:Extracellular Matrix / Q000737:chemistry; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010446:Peptide Fragments; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism; D013379:Substrate Specificity
C122077:CLEC3A protein, human; D037181:Lectins, C-Type; D010446:Peptide Fragments; D011509:Proteoglycans; D020783:Matrix Metalloproteinase 7