title: Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains.
abstract: Syndecans are transmembrane heparan sulfate proteoglycans with roles in cell proliferation, differentiation, adhesion, and migration. They have been associated with multiple functions in tumour progression, through their ability to interact with a wide range of ligands as well as other receptors, which makes them key effectors in the pericellular microenvironment. Extracellular shedding of syndecans by tumour-associated matrix metalloproteinases (MMPs) may have an important role in tumour progression. Such ectodomain shedding generates soluble ectodomains that may function as paracrine or autocrine effectors, or as competitive inhibitors of the intact proteoglycan. Tumour-associated MMPs are shown here to cleave the ectodomains of human syndecan-1 and syndecan-4. Two membrane proximal regions of both syndecan-1 and syndecan-4 are favoured MMP cleavage sites, six and 15 residues from the transmembrane domain. Other sites are 35-40 residues C-terminal from the heparan sulfate chain substitution sites in both syndecans. The MT1-MMP cleavage sites in syndecan-1 and syndecan-4 were confirmed by site-directed mutagenesis. These findings provide insights into the characteristics of syndecan shedding.
authors: Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors: Tina
authors: T
authors: Manon-Jensen
authors: Hinke A B
authors: HA
authors: Multhaupt
authors: John R
authors: JR
authors: Couchman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D004789:Enzyme Activation; D057075:Enzyme Assays / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D025941:Protein Interaction Mapping / Q000379:methods*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012995:Solubility; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; C508241:SDC1 protein, human; C508304:SDC4 protein, human; D053668:Syndecan-1; D053671:Syndecan-4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9