Shedding of Syndecan-1 and -4 Ectodomains Is Regulated by Multiple Signaling Pathways and Mediated by a Timp-3–Sensitive Metalloproteinase

Fitzgerald, Marilyn L.; Wang, Zihua; Park, Pyong Woo; Murphy, Gillian; Bernfield, Merton

doi:10.1083/jcb.148.4.811

Cited by 388 publications

(436 citation statements)

References 84 publications

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“…Unlike TIMP-1, TIMP-2 and TIMP-3 are effective inhibitors of MT-MMPs. In contrast to the other TIMPs, TIMP-3 is capable of inhibiting the shedding of cell-membrane-anchored proteins such as tumor necrosis factor (TNF) receptor, 15 interleukin-6 receptor, 16 syndecan ectodomains, 17 and of the TNF-a-converting enzyme (TACE). 36 The presence of TIMPs has been shown in RA synovial tissue.…”

Section: Introductionmentioning

confidence: 99%

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Laan

Quax

Seemayer³

et al. 2003

Gene Ther

103

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Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse coimplantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1-and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. In vitro, the number of invading cells was reduced to 25% (Po0.001) in the AdTIMP-1-transduced cells and to 13% (Po0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA.

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Section: Introductionmentioning

confidence: 99%

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Laan

Quax

Seemayer³

et al. 2003

Gene Ther

103

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“…The syndecan ectodomain is shed constitutively by cultured cells, though the release can be accelerated by growth factor receptor activation, e.g. by thrombin and epidermal growth factor 6,7). In vivo, stress or skin injury/wounding can lead to increased levels of soluble syndecan-1 ectodomain in biological fluids (7,8).…”

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confidence: 99%

“…In contrast, syndecan-1 overexpressing mice accumulate excessive amounts of shed syndecan-1 in skin wound fluids, which leads to a delay in wound repair concomitant with enhanced elastolytic activity, reduced cell proliferation rates and abnormal blood vessel morphology (8). Finally, shedding of syndecan ectodomains appears to modulate feeding behaviour and weight in rodents (14).The precise mechanism of syndecan-1 ectodomain shedding has not been elucidated, yet there is accumulating evidence which suggests that diverse signal transduction pathways, such as the protein kinase C (PKC), protein tyrosine kinase (PTK) and MAP kinase pathways, are involved (6,15,16). Inhibitors of PKC, PTK or MAP kinase can selectively inhibit the syndecan-1 ectodomains shedding (6).…”

mentioning

confidence: 99%

“…Inhibitors of PKC, PTK or MAP kinase can selectively inhibit the syndecan-1 ectodomains shedding (6). Previous work suggested that syndecan-1 ectodomain shedding appears to involve several metalloproteinases, since both a peptide hydroxamate metalloproteinases inhibitor and tissue inhibitor of metalloprotease-3 (TIMP-3) can specifically inhibit syndecan-1 ectodomain shedding (6). Peptide hydroxamates inhibit both constitutive and PMA-accelerated syndecan-1 ectodomain shedding, though TIMP-3 appears to inhibit only the PMA-accelerated shedding.…”

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confidence: 99%

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Constitutive and Accelerated Shedding of Murine Syndecan-1 Is Mediated by Cleavage of Its Core Protein at a Specific Juxtamembrane Site

et al. 2005

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Syndecan-1 is a developmentally regulated cell surface heparan sulfate proteoglycan (HSPG). It functions as a coreceptor for a variety of soluble and insoluble ligands and is implicated in several biological processes, including differentiation, cell migration, morphogenesis, and recently feeding behavior. The extracellular domain of syndecan-1 is proteolytically cleaved at a juxtamembrane site by tissue inhibitor of metalloprotease-3 (TIMP-3)-sensitive metalloproteinases in response to a variety of physiological stimulators and stress in a process known as shedding. Shedding converts syndecan-1 from a membrane-bound coreceptor into a soluble effector capable of binding the same ligands. We found that replacing the syndecan-1 juxtamembrane amino acid residues A243SQSL247 with human CD4 amino acid residues can completely block PMA-induced syndecan-1 ectodomain shedding. Furthermore, using Liquid Chromatography Electrospray Ionization Mass Spectrometry (LC-ESI-MS), we identified the proteolytic cleavage site of syndecan-1 to amino acids A243 and S244, generated by constitutive and PMA-induced shedding from murine NMuMG cells. Finally, we show that basal cleavage of syndecan-1 utilizes the same in vivo site as the in vitro site. Indeed, as predicted, transgenic mice expressing the syndecan-1/CD4 cDNA do not shed the syndecan-1 ectodomain in vivo. These results suggest that the same cleavage site is utilized for basal syndecan-1 ectodomain shedding both in vitro from NMuMG and CHO cells as well as in vivo. Keywords syndecan; shedding; cleavage site Syndecan-1 is one of four members of the syndecan family of heparan sulfate proteoglycans (1,2) Most cells express at least one type of syndecan, and their expression pattern is highly regulated (1,3). Syndecans are abundant on the surface of all adherent mammalian cells. About 1% of membrane-anchored proteins undergo regulated proteolytic cleavage near the plasma membrane, resulting in release of their ectodomains in a process known as shedding (4,5). The syndecan ectodomain is shed constitutively by cultured cells, though the release can be accelerated by growth factor receptor activation, e.g. by thrombin and epidermal growth factor 6,7). In vivo, stress or skin injury/wounding can lead to increased levels of soluble syndecan-1 ectodomain in biological fluids (7,8). The process of ectodomain shedding not only reduces the number of surface receptors, an effective way to down-regulate signal transduction through these receptors, it also converts the membrane-bound cell surface receptors into soluble effectors that can effectively compete for the same ligand as dominant negative modulators as well as act as paracrine effectors at a remote location. The significance of this has been shown in vivo in syndecan-1-deficient and syndecan-1 overexpressing mice, which lack or contain excessive amounts of soluble ectodomains in their tissues, respectively. Syndecan-1 deficient mice are resistant to Pseudomonas aeruginosa lung infections, due to the absence of soluble syn...

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“…Extracellular signal-regulated kinase (ERK) has been shown to mediate EGF-dependent shedding of syndecan-4 in immortalized endothelial and epithelial cells (12). To determine whether ERK activation was involved in the HPODE-dependent increase in syndecan-4 mRNA expression, ERK phosphorylation was examined using antibodies specific to the dual phosphorylated, active forms of p44 and p42 ERK.…”

Section: Activation Of Erk Is Required For Hpode-mediated Upregulatiomentioning

confidence: 99%

Oxidized linoleic acid regulates expression and shedding of syndecan-4

Houston

Julien

Parthasarathy³

et al. 2005

American Journal of Physiology-Cell Physiology

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Syndecan-4, a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic proatherogenic conditions such as those characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation, arterial smooth muscle cells were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid, oxidized products of linoleic acid, which is the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependent, rapid upregulation of syndecan-4 mRNA expression that was not attenuated by cycloheximide. This response was inhibited by pretreatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NF-κB. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase signaling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lipids.

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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

Cited by 388 publications

References 84 publications

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Constitutive and Accelerated Shedding of Murine Syndecan-1 Is Mediated by Cleavage of Its Core Protein at a Specific Juxtamembrane Site

Oxidized linoleic acid regulates expression and shedding of syndecan-4

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