title: Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase.
abstract: The syndecan family of four transmembrane heparan sulfate proteoglycans binds a variety of soluble and insoluble extracellular effectors. Syndecan extracellular domains (ectodomains) can be shed intact by proteolytic cleavage of their core proteins, yielding soluble proteoglycans that retain the binding properties of their cell surface precursors. Shedding is accelerated by PMA activation of protein kinase C, and by ligand activation of the thrombin (G-protein-coupled) and EGF (protein tyrosine kinase) receptors (Subramanian, S.V., M.L. Fitzgerald, and M. Bernfield. 1997. J. Biol. Chem. 272:14713-14720). Syndecan-1 and -4 ectodomains are found in acute dermal wound fluids, where they regulate growth factor activity (Kato, M., H. Wang, V. Kainulainen, M.L. Fitzgerald, S. Ledbetter, D.M. Ornitz, and M. Bernfield. 1998. Nat. Med. 4:691-697) and proteolytic balance (Kainulainen, V., H. Wang, C. Schick, and M. Bernfield. 1998. J. Biol. Chem. 273:11563-11569). However, little is known about how syndecan ectodomain shedding is regulated. To elucidate the mechanisms that regulate syndecan shedding, we analyzed several features of the process that sheds the syndecan-1 and -4 ectodomains. We find that shedding accelerated by various physiologic agents involves activation of distinct intracellular signaling pathways; and the proteolytic activity responsible for cleavage of syndecan core proteins, which is associated with the cell surface, can act on unstimulated adjacent cells, and is specifically inhibited by TIMP-3, a matrix-associated metalloproteinase inhibitor. In addition, we find that the syndecan-1 core protein is cleaved on the cell surface at a juxtamembrane site; and the proteolytic activity responsible for accelerated shedding differs from that involved in constitutive shedding of the syndecan ectodomains. These results demonstrate the existence of highly regulated mechanisms that can rapidly convert syndecans from cell surface receptors or coreceptors to soluble heparan sulfate proteoglycan effectors. Because the shed ectodomains are found and function in vivo, regulation of syndecan ectodomain shedding by physiological mediators indicates that shedding is a response to specific developmental and pathophysiological cues.
authors.affiliation: Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: P W
authors.initials: PW
authors.lastname: Park
authors.forename: G
authors.initials: G
authors.lastname: Murphy
authors.forename: M
authors.initials: M
authors.lastname: Bernfield
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D053668:Syndecan-1; D053671:Syndecan-4; D053667:Syndecans; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology*
chemical_list: D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D018179:Receptors, Thrombin; C508241:SDC1 protein, human; C508304:SDC4 protein, human; C508242:Sdc1 protein, mouse; C508306:Sdc4 protein, mouse; D053668:Syndecan-1; D053671:Syndecan-4; D053667:Syndecans; D019717:Tissue Inhibitor of Metalloproteinase-3; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate