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. 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. Syndecans are transmembrane heparan sulfate proteoglycans expressed on all adherent cells (1Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2361) Google Scholar, 2Rapraeger A.C. Ott V.L. Curr. Opin. Cell. Biol. 1998; 10: 620-628Crossref PubMed Scopus (102) Google Scholar) and have been proposed to play an important role in tissue morphogenesis by virtue of their ability to bind, via their covalently attached glycosaminoglycan chains, to a variety of extracellular adhesive molecules including fibronectin, thrombospondin, various collagens, and heparin-binding growth-associated molecules and growth factors such as basic fibroblast growth factor (3Perrimon N. Bernfield M. Nature. 2000; 404: 725-728Crossref PubMed Scopus (667) Google Scholar, 4Park P.W. Reizes O. Bernfield M. J. Biol. Chem. 2000; 275: 29923-29926Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 5Rapraeger A.C. J. Cell. Biol. 2000; 149: 995-998Crossref PubMed Scopus (177) Google Scholar, 6Perrimon N. Bernfield M. Semin. Cell Dev. Biol. 2001; 12: 65-67Crossref PubMed Scopus (102) Google Scholar, 7Rapraeger A.C. Semin. Cell Dev. Biol. 2001; 12: 107-116Crossref PubMed Scopus (109) Google Scholar, 8Woods A. J. Clin. Invest. 2001; 107: 935-941Crossref PubMed Scopus (115) Google Scholar). Since the expression of syndecans appears to be controlled during both development and the progression of tumor cells to the metastatic phenotype, it has been proposed that syndecans are important regulators of the migratory and invasive behaviors of both normal and transformed cells (9Bernfield M. Kokenyesi R. Kato M. Hinkes M.T. Spring J. Gallo R.L. Lose E.J. Annu. Rev. Cell Biol. 1992; 8: 365-393Crossref PubMed Scopus (988) Google Scholar, 10Inki P. Jalkanen M. Ann. Med. 1996; 28: 63-67Crossref PubMed Scopus (105) Google Scholar). The syndecan family is composed of four closely related proteins (syndecan-1, -2, -3, and -4) encoded by four different genes. Syndecan-1 is abundant in normal epithelial cells and tissues, localizing to both basal and suprabasal cell layers (1Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2361) Google Scholar). Disruption of syndecan-1 expression in cultured cells leads to an epithelial mesenchymal transformation, with associated changes in cell polarity and cell-cell adhesion and altered epithelium-specific gene expression (7Rapraeger A.C. Semin. Cell Dev. Biol. 2001; 12: 107-116Crossref PubMed Scopus (109) Google Scholar, 11Dobra K. Andang M. Syrokou A. Karamanos N.K. Hjerpe A. Exp. Cell Res. 2000; 258: 12-22Crossref PubMed Scopus (65) Google Scholar). The intact ectodomain of each syndecan is constitutively shed from cultured cells (12Kim C.W. Goldberger O.A. Gallo R.L. Bernfield M. Mol. Biol. Cell. 1994; 5: 797-805Crossref PubMed Scopus (358) Google Scholar, 13Spring J. Paine-Saunders S.E. Hynes R.O. Bernfield M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 3334-3338Crossref PubMed Scopus (122) Google Scholar) as part of normal cell surface heparan sulfate proteoglycan turnover (14Yanagishita M. Hascall V.C. J. Biol. Chem. 1992; 267: 9451-9454Abstract Full Text PDF PubMed Google Scholar). Ectodomain shedding appears to contribute to diverse pathophysiological events such as host defense, wound healing, arthritis, and Alzheimer's disease, but how shedding is regulated remains largely unknown (15Kiessling L.L. Gordon E.J. Chem. Biol. 1998; 5: R49-R62Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 16Merlos-Suarez A. Arribas J. Biochem. Soc. Trans. 1999; 27: 243-246Crossref PubMed Scopus (17) Google Scholar, 17Fitzgerald M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (352) Google Scholar). Matrix metalloproteinases (MMPs) 1The abbreviations used are: MMP, matrix metalloproteinase; GST, glutathione S-transferase; MT-MMP, membrane-type matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; TPA, 12-O-tetradecanoylphorbol-13-acetate; BB-94, 4-(N-hydroxyamino)-2R-iso-butyl-3-S-(thienylthiomethyl)-succinyl-l-phenylalanine-N-methylamide. are a family of Zn2+-dependent enzymes that are known to cleave extracellular matrix proteins in normal and pathological conditions (18Birkedal H.H. Moore W.G. Bodden M.K. Windsor L.J. Birkedal H.B. DeCarlo A. Engler J.A. Crit. Rev. Oral Biol. Med. 1993; 4: 197-250Crossref PubMed Scopus (2677) Google Scholar, 19Woessner J.F.J. FASEB J. 1991; 5: 2145-2154Crossref PubMed Scopus (3125) Google Scholar, 20Seiki M. APMIS. 1999; 107: 137-143Crossref PubMed Scopus (276) Google Scholar). 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Recently, matrilysin (MMP-7) was shown to mediate shedding of syndecan-1/a CXC chemokine (KC) complex from the mucosal surface, which directs and confines to in Park P.W. Wilson C.L. W.C. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). have an expression cloning method to the of which not by MT1-MMP but also as of MT1-MMP H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. H. J. Sato H. Cancer Res. 2001; Google Scholar, H. H. M. Okada Y. Seiki M. Sato H. PubMed Scopus Google Scholar). In have identified syndecan-1 as a of MT1-MMP and demonstrated that shedding of syndecan-1 by MT1-MMP stimulates cell migration. was from were by human placenta cDNA library in the expression was from Recombinant MT1-MMP and MT3-MMP with at the were as Sato H. Okada A. E. Imai K. Okada Y. Seiki M. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Nakamura H. E. Y. Y. Sato H. Seiki M. Okada Y. J. Biochem. 1999; PubMed Scopus Google Scholar). Recombinant TIMP-2 and were from and were from and was a from Cell HEK293T and fibrosarcoma HT1080 cells were from and cultured in with cloning to the of which with MMP-2, or MT1-MMP, was as H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). and an expression syndecan-1 was with either MT1-MMP or control into cells cultured in dishes to the was with and cells were a further Syndecan-1 was from the or cell by as K. N. Kato H. K. H. C. J. A. Cancer Res. 1995; 55: Google Scholar, C. M. A. J. 1999; PubMed Scopus Google Scholar). syndecan-1 was on and membrane The membrane was with in and with in Syndecan-1 was with as a and with as a in The was by an expression syndecan-1 was with either MT1-MMP or control into cells cultured in as The and cell were by the method M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (352) Google Scholar, Fitzgerald M.L. Bernfield M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and syndecan-1 was as HT1080 cells stably syndecan-1 were by cells transfected with syndecan-1 cDNA in in syndecan-1 and MT1-MMP were with or control into cells cultured in dishes with with type syndecan-1 was and with as H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). was with was of Recombinant Syndecan-1 cDNA was by a with an at and a with an at cDNA a syndecan-1 protein in which Gly245 was with Leu was by of syndecan-1 cDNA which The was with and and into the and of H. H. M. Okada Y. Seiki M. Sato H. PubMed Scopus Google Scholar). protein was by a cDNA at the of the as H. H. M. Okada Y. Seiki M. Sato H. PubMed Scopus Google Scholar). The was transformed with and the protein expression was induced by were and in Syndecan-1 protein with was from the by a Syndecan-1 proteins were to the of the of Syndecan-1 syndecan-1 protein was with recombinant MT1-MMP in of at and were on and to membrane The of each was the Migration HT1080 cells or cells were dishes with were with a in to cells and cultured in further cells were and at each H. H. M. Okada Y. Seiki M. Sato H. PubMed Scopus Google Scholar). of cDNA from the human placenta cDNA library was with MMP-2, and MT1-MMP cDNA into and cell were by with MMP-2, and MT1-MMP cDNA into cells a of a of and a of of a of cDNA of to the cDNA of from cDNA were by a of which induced to the not The of all cDNA was and the of the cDNA was that cDNA the transmembrane heparan sulfate proteoglycan syndecan-1 Shedding of Syndecan-1 by of by MT1-MMP by the expression of syndecan-1 was it a MT1-MMP and syndecan-1. Thus, syndecan-1 as a of Syndecan-1 was with MT1-MMP in and the shedding of syndecan-1 into or with cells was by and Syndecan-1 was spontaneously shed into from cells transfected with the syndecan-1 as a from to more than of the syndecan-1 was in cell which slower than that in the Co-expression of MT1-MMP syndecan-1 shedding and reduced level in the cell Treatment of cells with the MMP inhibitor BB-94 the shedding of syndecan-1 by MT1-MMP expression. Treatment of cells with also shedding of syndecan-1 as reported M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (352) Google Scholar, A.J. Biochem. J. 1997; PubMed Scopus Google Scholar). To syndecan-1 shedding induced by and MT1-MMP, of MMP BB-94, and TIMP-2 were and Shedding of syndecan-1 induced by either treatment or MT1-MMP expression was inhibited by the of BB-94, but TIMP-1 In contrast, the of recombinant TIMP-2 syndecan-1 shedding induced by MT1-MMP expression but not that by These results that a endogenous of syndecan-1 shedding in cells that is different from Shedding of syndecan-1 induced by and MT1-MMP was also by of cells The surface of cells transfected with the syndecan-1 cDNA was syndecan-1 with Syndecan-1 was also on the surface of cells with the MT1-MMP Treatment with BB-94 a syndecan-1 on cells with or with Co-expression of TIMP-2 or syndecan-1 of cells with the MT1-MMP but of TIMP-1 of syndecan-1 by treatment was by the expression of but not by the expression of TIMP-1 or TIMP-2. These results further that the syndecan-1 shedding is to different from MT1-MMP were with type their to shedding of syndecan-1 MT1-MMP in not syndecan-1 of the or shedding, but of the with that of not MT1-MMP also to syndecan-1 These results suggest that MT1-MMP with syndecan-1 through and that cell surface of MT1-MMP is the shedding of syndecan-1. other of the family were their to shedding of syndecan-1 the MT1-MMP and MT3-MMP promoted syndecan-1 shedding with a of Syndecan-1 by syndecan-1 ectodomain protein with at the was with recombinant MT1-MMP and was on The product of and a of were of was by the the that syndecan-1 ectodomain protein with at the is preferentially cleaved at the to the To the cleavage recombinant syndecan-1 ectodomain protein to was and with recombinant MT1-MMP The product was a the of which demonstrated the cleavage of Gly245-Leu246 peptide bond of syndecan-1. protein in which Gly245 was with Leu was with recombinant MT1-MMP, which not a but a of The of the by of or the cleavage of peptide bond of syndecan-1 by of protein with MT3-MMP a including other not Syndecan-1 Shedding Cell syndecan-1 cDNA was stably transfected into HT1080 fibrosarcoma cells (HT1080/SDC), which express of endogenous MT1-MMP H. Okada Y. J. A. E. Seiki M. Nature. 1994; 370: PubMed Scopus Google Scholar), and syndecan-1 shed into or associated with cells was by and HT1080/SDC cells shed a level of which was by as a slower that that from and the syndecan-1 concentration in cell was treatment of HT1080/SDC cells induced further syndecan-1 shedding and reduced the level of cell-associated syndecan-1. In contrast, treatment of cells with BB-94 syndecan-1 shedding, in syndecan-1 accumulation in the cells. shedding of syndecan-1 from HT1080/SDC cells was also by TIMP-2 but not by TIMP-1 as shown by shedding from HT1080/SDC cells was inhibited by HT1080/SDC cells were also by syndecan-1 Syndecan-1 was on HT1080/SDC cell surface, and treatment with BB-94 induced accumulation of syndecan-1 on the cell of was in HT1080/SDC cells but not in cells not The of TIMP-2 but not TIMP-1 significantly cell surface of syndecan-1. of HT1080/SDC cells on collagen-coated dishes was in the of HT1080 cells was inhibited by the of BB-94 or TIMP-2 and of Migration of HT1080/SDC cells was of cells. Treatment of HT1080/SDC cells with BB-94 or TIMP-2 further to and of the HT1080/SDC Syndecan-1 Shedding through the of Gly245-Leu246 syndecan-1 and with an of Gly245 with Leu were shedding by MT1-MMP expression Shedding of induced by MT1-MMP expression or treatment was significantly than that of syndecan-1. shedding from HT1080 cells stably was than that from HT1080/SDC and the level of cell-associated syndecan-1 in cells was than that of HT1080/SDC cells The concentration of syndecan-1 in cells by BB-94 treatment was at a with the level of cell-associated of cells was significantly slower than that of HT1080/SDC cells BB-94 of HT1080/SDC but of was not significantly by have identified and as molecules that with MMPs by the expression cloning H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. H. J. Sato H. Cancer Res. 2001; Google Scholar, H. H. M. Okada Y. Seiki M. Sato H. PubMed Scopus Google Scholar). In the identified that expression of the syndecan-1 gene also promoted of the to the in the by MT1-MMP in cells. Since endogenous TIMP-2 in cells are through the of complex and MT1-MMP, concentration of the complex by syndecan-1 H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). the of syndecan-1 expression on by MT1-MMP was with that of expression not H. Y. H. Itoh Y. Seiki M. Sato H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). a not directs MT1-MMP to but also as a MT1-MMP M. Itoh Y. Mori H. Okada A. H. Seiki M. J. Cell Biol. 2001; PubMed Scopus Google Scholar, H. N. M. Itoh Y. Sato H. H. I. Seiki M. J. 2002; PubMed Scopus Google Scholar), which to syndecan-1 is also cleaved by Co-expression of MT1-MMP with syndecan-1 promoted shedding of and the concentration of cell surface syndecan-1 was reduced. The of syndecan-1 shedding was also with but not with other MT-MMPs. of MT1-MMP that cell surface is the shedding of syndecan-1. of the of MT1-MMP syndecan-1 shedding, which the of MT1-MMP with syndecan-1 through Syndecan-1 ectodomain shedding was also by Syndecan-1 shedding by either MT1-MMP or was inhibited by both BB-94 and TIMP-2 syndecan-1 shedding promoted by MT1-MMP, and were inhibited by These results that syndecan-1 shedding induced by is by other than shedding of syndecan-1 ectodomain results from cleavage at a in core protein M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (352) Google Scholar). of the cleavage of syndecan-1 by MT1-MMP or MT3-MMP recombinant proteins was the Gly245-Leu246 peptide bond a of Gly245 with Leu significantly reduced shedding promoted by MT1-MMP expression or that the Gly245-Leu246 peptide bond is of the cleavage shedding promoted by MT1-MMP expression or Gly245-Leu246 of human syndecan-1 to in syndecan-1. remains to be syndecan-1 is cleaved at by to extracellular matrix proteins including and the migratory and invasive of both normal and transformed cells (9Bernfield M. Kokenyesi R. Kato M. Hinkes M.T. Spring J. Gallo R.L. Lose E.J. Annu. Rev. Cell Biol. 1992; 8: 365-393Crossref PubMed Scopus (988) Google Scholar, 10Inki P. Jalkanen M. Ann. Med. 1996; 28: 63-67Crossref PubMed Scopus (105) Google Scholar). expression of syndecan-1 in epithelial tumor cells an epithelial and growth S. M. Jalkanen M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). 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Imai K. 2001; 91: PubMed Scopus Google Scholar). Syndecans are also known to to various growth factors and via glycosaminoglycan and A.C. J. Cell. Biol. 2000; 149: 995-998Crossref PubMed Scopus (177) Google Scholar, 6Perrimon N. Bernfield M. Semin. Cell Dev. Biol. 2001; 12: 65-67Crossref PubMed Scopus (102) Google Scholar, 8Woods A. J. Clin. Invest. 2001; 107: 935-941Crossref PubMed Scopus (115) Google Scholar). Thus, shedding of syndecan-1 with factors and the of shed with factors be of the important the of their in various pathophysiological Recently, matrilysin was shown to mediate shedding of a syndecan-1/a CXC chemokine (KC) complex from the mucosal surface, which directs and confines to of in Park P.W. Wilson C.L. W.C. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). MT1-MMP is also expressed in diverse pathophysiological conditions and contribute to the of from growth factors and by shedding syndecan-1 with In have shown that MT1-MMP and syndecan-1 which cell on Since syndecan-1 shedding is in diverse pathological events such as tumor wound healing, arthritis, and Alzheimer's disease, the of shedding contribute to the development of and E. of of the