Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration.
The transmembrane heparan sulfate proteoglycan syndecan-1 was identified from a human placenta cDNA library by the expression cloning method as a gene product that interacts with membrane type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with syndecan-1 in HEK293T cells promoted syndecan-1 shedding, and concentration of cell-associated syndecan-1 was reduced. Treatment of cells with MMP inhibitor BB-94 or tissue inhibitor of MMP (TIMP)-2 but not TIMP-1 interfered with the syndecan-1 shedding promoted by MT1-MMP expression. In contrast, syndecan-1 shedding induced by 12-O-tetradecanoylphorbol-13-acetate treatment was inhibited by BB-94 but not by either TIMP-1 or TIMP-2. Shedding of syndecan-1 was also induced by MT3-MMP but not by other MT-MMPs. Recombinant syndecan-1 core protein was shown to be cleaved by recombinant MT1-MMP or MT3-MMP preferentially at the Gly245-Leu246 peptide bond. HT1080 fibrosarcoma cells stably transfected with the syndecan-1 cDNA (HT1080/SDC), which express endogenous MT1-MMP, spontaneously shed syndecan-1. Migration of HT1080/SDC cells on collagen-coated dishes was significantly slower than that of control HT1080 cells. Treatment of HT1080/SDC cells with BB-94 or TIMP-2 induced accumulation of syndecan-1 on the cell surface, concomitant with further retardation of cell migration. Substitution of Gly245 of syndecan-1 with Leu significantly reduced shedding from HT1080/SDC cells and cell migration. These results suggest that the shedding of syndecan-1 promoted by MT1-MMP through the preferential cleavage of Gly245-Leu246 peptide bond stimulates cell migration.
Endo
Kazuhira
K
Department of Molecular Virology and Oncology, Cancer Research Institute, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
Takino
Takahisa
T
Miyamori
Hisashi
H
Kinsen
Hidenori
H
Yoshizaki
Tomokazu
T
Furukawa
Mitsuru
M
Sato
Hiroshi
H
D001665:Binding Sites; D002273:Carcinogens; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D000939:Epitopes; D015723:Gene Library; D005998:Glycine / Q000737:chemistry; D006801:Humans; D007930:Leucine / Q000737:chemistry; D053513:Matrix Metalloproteinase 16; D053504:Matrix Metalloproteinases, Membrane-Associated; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D053668:Syndecan-1; D053667:Syndecans; D013755:Tetradecanoylphorbol Acetate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014162:Transfection; D014945:Wound Healing
D002273:Carcinogens; D018076:DNA, Complementary; D000939:Epitopes; C507102:MMP16 protein, human; D008562:Membrane Glycoproteins; D010455:Peptides; D011509:Proteoglycans; D011994:Recombinant Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D053513:Matrix Metalloproteinase 16; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D007930:Leucine; D013755:Tetradecanoylphorbol Acetate; D005998:Glycine