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Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase.

Fitzgerald ML, Wang Z, Park PW, Murphy G, Bernfield M - J. Cell Biol. (2000)

Bottom Line: Ledbetter, D.M.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

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Syndecan ectodomain shedding. The syndecan ectodomains can be shed intact by proteolytic cleavage of their core proteins, yielding soluble HSPGs that retain the binding properties of their cell surface counterparts. Shedding of syndecan-1 and -4 ectodomains from the cell surface is accelerated by PMA and a variety of physiological effectors (e.g., EGF family members, thrombin, hyperosmolarity, sphingomyelinase, and ceramide) via activation of multiple intracellular signaling pathways. These signals converge on a TIMP-3–sensitive cell surface metalloproteinase system that cleaves the core protein within 15 amino acids of the cell surface, and can act on unstimulated adjacent cells. Shedding is stimulated by tissue injury and these syndecan ectodomains are found in inflammatory fluids (Subramanian et al. 1997) where they modulate the activities of growth factors and proteinases (Kainulainen et al. 1998; Kato et al. 1998). See text for details.
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Figure 11: Syndecan ectodomain shedding. The syndecan ectodomains can be shed intact by proteolytic cleavage of their core proteins, yielding soluble HSPGs that retain the binding properties of their cell surface counterparts. Shedding of syndecan-1 and -4 ectodomains from the cell surface is accelerated by PMA and a variety of physiological effectors (e.g., EGF family members, thrombin, hyperosmolarity, sphingomyelinase, and ceramide) via activation of multiple intracellular signaling pathways. These signals converge on a TIMP-3–sensitive cell surface metalloproteinase system that cleaves the core protein within 15 amino acids of the cell surface, and can act on unstimulated adjacent cells. Shedding is stimulated by tissue injury and these syndecan ectodomains are found in inflammatory fluids (Subramanian et al. 1997) where they modulate the activities of growth factors and proteinases (Kainulainen et al. 1998; Kato et al. 1998). See text for details.

Mentions: Diverse agonists were identified as accelerators of syndecan-1 and -4 ectodomain shedding (Fig. 11). Shedding accelerated by activation of the EGF and thrombin receptors correlates best with activation of the ERK MAP kinase pathway, but does not appear to involve PKC activation. In contrast, agonists associated with cellular stress (e.g., hyperosmolarity and ceramide) appear to require PKC activation upstream of the JNK/SAPK MAP kinase pathway. Inhibition of p38 MAP kinase activity by SB 202190 had limited effect on shedding accelerated by any of the agonists tested. Taken together, these results strongly correlate syndecan ectodomain shedding with the action of specific MAP kinase signaling pathways.


Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase.

Fitzgerald ML, Wang Z, Park PW, Murphy G, Bernfield M - J. Cell Biol. (2000)

Syndecan ectodomain shedding. The syndecan ectodomains can be shed intact by proteolytic cleavage of their core proteins, yielding soluble HSPGs that retain the binding properties of their cell surface counterparts. Shedding of syndecan-1 and -4 ectodomains from the cell surface is accelerated by PMA and a variety of physiological effectors (e.g., EGF family members, thrombin, hyperosmolarity, sphingomyelinase, and ceramide) via activation of multiple intracellular signaling pathways. These signals converge on a TIMP-3–sensitive cell surface metalloproteinase system that cleaves the core protein within 15 amino acids of the cell surface, and can act on unstimulated adjacent cells. Shedding is stimulated by tissue injury and these syndecan ectodomains are found in inflammatory fluids (Subramanian et al. 1997) where they modulate the activities of growth factors and proteinases (Kainulainen et al. 1998; Kato et al. 1998). See text for details.
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Figure 11: Syndecan ectodomain shedding. The syndecan ectodomains can be shed intact by proteolytic cleavage of their core proteins, yielding soluble HSPGs that retain the binding properties of their cell surface counterparts. Shedding of syndecan-1 and -4 ectodomains from the cell surface is accelerated by PMA and a variety of physiological effectors (e.g., EGF family members, thrombin, hyperosmolarity, sphingomyelinase, and ceramide) via activation of multiple intracellular signaling pathways. These signals converge on a TIMP-3–sensitive cell surface metalloproteinase system that cleaves the core protein within 15 amino acids of the cell surface, and can act on unstimulated adjacent cells. Shedding is stimulated by tissue injury and these syndecan ectodomains are found in inflammatory fluids (Subramanian et al. 1997) where they modulate the activities of growth factors and proteinases (Kainulainen et al. 1998; Kato et al. 1998). See text for details.
Mentions: Diverse agonists were identified as accelerators of syndecan-1 and -4 ectodomain shedding (Fig. 11). Shedding accelerated by activation of the EGF and thrombin receptors correlates best with activation of the ERK MAP kinase pathway, but does not appear to involve PKC activation. In contrast, agonists associated with cellular stress (e.g., hyperosmolarity and ceramide) appear to require PKC activation upstream of the JNK/SAPK MAP kinase pathway. Inhibition of p38 MAP kinase activity by SB 202190 had limited effect on shedding accelerated by any of the agonists tested. Taken together, these results strongly correlate syndecan ectodomain shedding with the action of specific MAP kinase signaling pathways.

Bottom Line: Ledbetter, D.M.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Newborn Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

Show MeSH
Related in: MedlinePlus