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

Chen, Keyang; Williams, Kevin Jon

doi:10.1074/jbc.m112.444737

Cited by 69 publications

(92 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…thus bringing HSPGs-mediated endocytotic vesicles into the cells (39). Collectively, our data imply that exogenous latent heparanase enters cardiomyocytes through the HSPG-dependent caveolae pathway.…”

Section: Discussionmentioning

confidence: 71%

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

et al. 2014

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 71%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…(2) Two adhesion gene families (syndecan and protocadherin) were expanded in the genome of B. platifrons, and these families have been reported to mediate endocytosis in other species 23,24 ( Supplementary Figs 21 and 22). (3) Positive selection of six genes in the endocytosis pathway was shown by a branch-site evolutionary analysis ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Adaptation to deep-sea chemosynthetic environments as revealed by mussel genomes

et al. 2017

View full text Add to dashboard Cite

Hydrothermal vents and methane seeps are extreme deep-sea ecosystems that support dense populations of specialized macro benthos such as mussels. But the lack of genome information hinders the understanding of the adaptation of these animals to such inhospitable environments. Here we report the genomes of a deep-sea vent/seep mussel (Bathymodiolus platifrons) and a shallow-water mussel (Modiolus philippinarum). Phylogenetic analysis shows that these mussel species diverged approximately 110.4 million years ago. Many gene families, especially those for stabilizing protein structures and removing toxic substances from cells, are highly expanded in B. platifrons, indicating adaptation to extreme environmental conditions. The innate immune system of B. platifrons is considerably more complex than that of other lophotrochozoan species, including M. philippinarum, with substantial expansion and high expression levels of gene families that are related to immune recognition, endocytosis and caspase-mediated apoptosis in the gill, revealing presumed genetic adaptation of the deep-sea mussel to the presence of its chemoautotrophic endosymbionts. A follow-up metaproteomic analysis of the gill of B. platifrons shows methanotrophy, assimilatory sulfate reduction and ammonia metabolic pathways in the symbionts, providing energy and nutrients, which allow the host to thrive. Our study of the genomic composition allowing symbiosis in extremophile molluscs gives wider insights into the mechanisms of symbiosis in other organisms such as deep-sea tubeworms and giant clams.

show abstract

“…The role of caveolae in endothelial nitrous oxide synthase activation, which results in increased NO production and resultant increases in cGMP (55), and the colocalization of the heparin receptor with caveolin-1 (28) suggest that these players could be linked in modulating healthy endothelial function. The HSPG syndecan-1 requires caveolae for uptake (56), indicating that it might interact with TMEM184A in caveolae. TNF␣ has been shown to inhibit endothelial nitrous oxide synthase activity and, as a result, decrease NO production, which would lead to lower levels of active cGMP-dependent protein kinase.…”

Section: Discussionmentioning

confidence: 99%

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Farwell

Kanyi

Hamel

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparininduced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNF␣-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNF␣-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity.For almost 100 years heparin has been used as an anticoagulant. Specific heparin interactions with proteins important in the anti-clotting system are now well understood. Many heparin binding proteins, including quite a few involved in modulating vascular function, inflammation, and angiogenesis, have been identified (reviewed in Ref. 1). The large number of reports indicating evidence of decreased endogenous heparin and heparan sulfates (HS) 3 in atherosclerosis (in model animals and human disease) led to a proposal that decreases in endogenous heparins might be important in the development of atherosclerosis (2). More recent evidence in support of that hypothesis includes increased heparanase expression in atherosclerosis (reviewed in Ref.3) and increased levels of glycocalyx heparan sulfate in regions of the vasculature where laminar flow decreases the likelihood of atherosclerosis development (4).In addition to heparin, heparin binding proteins typically also bind HS chains on HS proteoglycans (HSPGs). Although the carbohydrate backbones of heparin and HS are identical, modifications and sulfation patterns vary. HS chains have fewer sulfate residues per disaccharide and a lower overall charge, but their widespread expression suggests that HS may provide many in vivo functions identified originally as heparin functions (reviewed in Ref. 5). Heparin binding to growth factors modulates their activity and appears to protect them from degradation...

show abstract

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

Cited by 69 publications

References 57 publications

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

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

Adaptation to deep-sea chemosynthetic environments as revealed by mussel genomes

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Contact Info

Product

Resources

About