Activation of ERK signaling upon alternative protease nexin‐1 internalization mediated by syndecan‐1

Li, Xiaobiao; Herz, Joachim; Monard, Denis

doi:10.1002/jcb.20881

Cited by 24 publications

(22 citation statements)

References 72 publications

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“…PN-1 is known to be expressed by fibroblasts from many different tissue types, including foreskin fibroblasts, 6 skin fibroblasts, 8 or mouse embryonic fibroblasts. 24 In human foreskin fibroblasts, PN-1 expression has been shown to be upregulated by interleukin-1. 25 We showed here that TGF-b, a potent profibrogenic cytokine, could also upregulate PN-1 expression in lung fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

François

Vénisse

Marchal-Sommé

et al. 2014

Laboratory Investigation

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Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 (PN-1) is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, thrombin and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during IPF. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with IPF. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-b, a major pro-fibrotic cytokine involved in IPF. Another serpin, plasminogen activator inhibitor-1 (PAI-1) is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from IPF and stimulated fibroblasts were shown to inhibit efficiently thrombin activity, indicating that both serpins should exhibit complementary roles in IPF pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased fibronectin expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased fibronectin expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on fibronectin expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of IPF by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in IPF and could therefore give rise to new therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

François

Vénisse

Marchal-Sommé

et al. 2014

Laboratory Investigation

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“…We began with ERK activation, because it can occur after ligand binding (30) and was reported to be an early event during syndecan-1-mediated internalization (Ͻ10 min) (31). Previous studies did not indicate which site(s) on ERK became phosphorylated upon syndecan engagement.…”

Section: Mkkk Motif Mediates Basal Association With ␣-Tubulin Rapid mentioning

confidence: 99%

Molecular Mediators for Raft-dependent Endocytosis of Syndecan-1, a Highly Conserved, Multifunctional Receptor

Chen

Williams

2013

Journal of Biological Chemistry

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Background: Endocytosis via rafts remains incompletely characterized. Results: Raft-dependent endocytosis of syndecan-1 occurs in two phases, each requiring a kinase and a corresponding cytoskeletal partner. Each phase depends on MKKK, a novel, conserved motif within syndecan-1. Conclusion: These findings demonstrate the molecular choreography behind endocytosis of a raft-dependent receptor. Significance: Syndecans mediate uptake of biologically and medically important ligands.

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“…For studying the mechanism of internalization, 350 mmol/L sucrose or 1 mg/mL filipin was applied to myocytes for 15 min before latent heparanase to block clathrin-coated pits and caveolae-dependent internalization, respectively (21,22). Dynasore (0-25 mmol/L) or genistein (0-100 mmol/L) for 1 h were also used to inhibit dynamin and tyrosine kinase activity, respectively, which could be involved in internalization of exogenous heparanase (23,24). Chloroquine (200 mmol/L) was used to inhibit lysosomal enzymes, and myocytes were incubated for 2 h. Anacardic acid (10 mmol/L) was used to inhibit HAT activity.…”

Section: Treatmentsmentioning

confidence: 99%

“…To determine binding and uptake of heparanase by myocytes, total cell lysates were collected to detect heparanase by Western blot. For measuring internalization of heparanase, plasma membrane was removed by a procedure described previously (24). Briefly, myocytes were lysed in 50 mmol/L Tris-HCl (pH 7.5), 150 mmol/L NaCl, 0.2 mol/L sucrose, 2 mmol/L EDTA, 2 mmol/L EGTA, and protease inhibitor cocktail (Roche) and centrifuged at 10,000g at 4°C for 10 min.…”

Section: Uptake Of Exogenous Heparanasementioning

confidence: 99%

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Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen After Diabetes

et al. 2014

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After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway us ing HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.In diabetes, because glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) exclusively for ATP generation (1). Multiple adaptive mechanisms, either whole-body or intrinsic to the heart, operate to make this achievable, with hydrolysis of triglyceride-rich lipoproteins being the major source of FA to the diabetic heart (2). This critical reaction is catalyzed by the vascular content of lipoprotein lipase (LPL), and we were the first to report significantly higher coronary LPL activity after diabetes (3). In the heart, LPL is synthesized by cardiomyocytes, transported to heparan sulfate (HS) proteoglycan (HSPG) binding sites on the myocyte surface, and from this temporary reservoir, the enzyme is transferred across the interstitial space to reach endothelial cells (EC) (4,5). Before this transfer, liberation of HSPG-sequestered LPL is a prerequisite and is facilitated by heparanase, an EC endoglycosidase that can cleave HS side chains on HSPGs in the extracellular matrix and on the cell surface to release bound proteins (6).Heparanase is synthesized as a latent 65-kDa precursor. After its secretion and reuptake (7), heparanase enters

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Activation of ERK signaling upon alternative protease nexin‐1 internalization mediated by syndecan‐1

Cited by 24 publications

References 72 publications

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression

Molecular Mediators for Raft-dependent Endocytosis of Syndecan-1, a Highly Conserved, Multifunctional Receptor

Endothelial Cell Heparanase Taken Up by Cardiomyocytes Regulates Lipoprotein Lipase Transfer to the Coronary Lumen After Diabetes

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