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Renato V Iozzo - One of the best experts on this subject based on the ideXlab platform.
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Decorin interacting network : a comprehensive analysis of Decoring-binding partners and their versatile functions
Matrix Biology, 2016Co-Authors: Maria A. Gubbiotti, Sylvain D. Vallet, Sylvie Ricard-blum, Renato V IozzoAbstract:Decorin, a prototype small leucine-rich proteoglycan, regulates a vast array of cellular processes including collagen fibrillogenesis, wound repair, angiostasis, tumor growth, and autophagy. This functional versatility arises from a wide array of Decorin/protein interactions also including interactions with its single glycosaminoglycan side chain. The Decorin-binding partners encompass numerous categories ranging from extracellular matrix molecules to cell surface receptors to growth factors and enzymes. Despite the diversity of the Decorin interacting network, two main roles emerge as prominent themes in Decorin function: maintenance of cellular structure and outside-in signaling, culminating in anti-tumorigenic effects. Here we present contemporary knowledge regarding the Decorin interacting network and discuss in detail the biological relevance of these pleiotropic interactions, some of which could be targeted by therapeutic interventions.
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Decorin as a multivalent therapeutic agent against cancer
Advanced drug delivery reviews, 2015Co-Authors: Thomas Neill, Liliana Schaefer, Renato V IozzoAbstract:Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble Decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, Decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, Decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, Decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, Decorin would be an ideal therapeutic candidate for combating solid malignancies.
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the dermatan sulfate proteoglycan Decorin modulates α2β1 integrin and the vimentin intermediate filament system during collagen synthesis
PLOS ONE, 2012Co-Authors: Oliver Jungmann, Rick T Owens, Renato V Iozzo, Katerina Nikolovska, Christian Stock, Janniklas Schulz, Beate Eckes, Christoph Riethmuller, Daniela G SeidlerAbstract:Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of Decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn−/−) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn−/− mice could be rescued in vitro by Decorin but not with Decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn−/− fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of Decorin. We discovered that a Decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn−/− fibroblasts. This phenotype could be rescued by the Decorin proteoglycan but less efficiently by the Decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn−/− fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the Decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan Decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn−/−. Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that Decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn−/− phenotype.
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Decorin antagonizes the angiogenic network concurrent inhibition of met hypoxia inducible factor 1α vascular endothelial growth factor a and induction of thrombospondin 1 and timp3
Journal of Biological Chemistry, 2012Co-Authors: Thomas Neill, Rick T Owens, Liliana Schaefer, Hannah Painter, Simone Buraschi, Michael P Lisanti, Renato V IozzoAbstract:Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated Decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound Decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with Decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous Decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, Decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for Decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.
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Decorin mediated inhibition of colorectal cancer growth and migration is associated with e cadherin in vitro and in mice
Carcinogenesis, 2012Co-Authors: Nicole M Pohl, Renato V Iozzo, Zhibin Qian, George R Yang, Yuan Gou, Grace Guzman, Andre Kajdacsyballa, Wancai YangAbstract:Previous studies have shown that Decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the Decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27kip1 and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of Decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435–1440]. However, the regulation of E-cadherin by Decorin and its implication in cancer formation and metastasis is largely unknown. Using a Decorin knockout mouse model (Dcn−/− mice) and manipulated expression of Decorin in human colorectal cancer cells, we found that E-cadherin, a protein that regulates cell–cell adhesion, epithelial–mesenchymal transition and metastasis, was almost completely lost in Dcn−/− mouse intestine, and loss of Decorin and E-cadherin accelerated colon cancer cell growth and invasion in Dcn−/− mice. However, increasing Decorin expression in colorectal cancer cells attenuated cancer cell malignancy, including inhibition of cancer cell proliferation, promotion of apoptosis and importantly, attenuation of cancer cell migration. All these changes were linked to the regulation of E-cadherin by Decorin. Moreover, overexpression of Decorin upregulated E-cadherin through increasing of E-cadherin protein stability as E-cadherin messenger RNA and promoter activity were not affected. Co-immunoprecipitation assay showed a physical binding between Decorin and E-cadherin proteins. Taken together, our results provide direct evidence that Decorin-mediated inhibition of colorectal cancer growth and migration are through the interaction with and stabilization of E-cadherin.
Daniela G Seidler - One of the best experts on this subject based on the ideXlab platform.
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the dermatan sulfate proteoglycan Decorin modulates α2β1 integrin and the vimentin intermediate filament system during collagen synthesis
PLOS ONE, 2012Co-Authors: Oliver Jungmann, Rick T Owens, Renato V Iozzo, Katerina Nikolovska, Christian Stock, Janniklas Schulz, Beate Eckes, Christoph Riethmuller, Daniela G SeidlerAbstract:Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of Decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn−/−) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn−/− mice could be rescued in vitro by Decorin but not with Decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn−/− fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of Decorin. We discovered that a Decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn−/− fibroblasts. This phenotype could be rescued by the Decorin proteoglycan but less efficiently by the Decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn−/− fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the Decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan Decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn−/−. Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that Decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn−/− phenotype.
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The galactosaminoglycan-containing Decorin and its impact on diseases.
Current opinion in structural biology, 2012Co-Authors: Daniela G SeidlerAbstract:Decorin, a member of the small leucine-rich proteoglycans, is involved in many physiological and pathological processes. Decorin functions not only as structural molecule in organizing the extracellular matrix but also as signaling molecule controlling cell growth, morphogenesis and immunity. Mutations in Decorin or alterations in the post-translational modifications of the glycosaminoglycan (GAG) chain lead to connective tissue disorders such as the congenital stromal corneal dystrophy and the Ehlers-Danlos syndrome. The summarized data reveal that Decorin has a large impact on biological processes also because of the complex structure of the GAG chain. The complexity of Decorin also covers the binding and sequestering of growth factors and their signaling. This shows that the Decorin protein and the dermatan sulfate chain of Decorin have both a structural function and a signaling function. Since defects in the biosynthesis of either the protein core or the GAG chain lead to structural alterations in the extracellular matrix and changes in the protein expression profile of the cells embedded in the matrix, this review focuses on the insights of structural function of Decorin and includes data about dermatan sulfate.
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An Antimetastatic Role for Decorin in Breast Cancer
The American journal of pathology, 2008Co-Authors: Silvia Goldoni, David J Mcquillan, Daniela G Seidler, Rick T Owens, Jack Heath, Matteo Fassan, Raffaele Baffa, Mathew L. Thakur, Renato V IozzoAbstract:Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of Decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that Decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When Decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human Decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both Decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly, systemic delivery of Decorin prevented metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative assays. In contrast, AG879 failed to have any effect. Our data support a role for Decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.
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the glycosaminoglycan chain of Decorin plays an important role in collagen fibril formation at the early stages of fibrillogenesis
FEBS Journal, 2007Co-Authors: Claus Ruhland, Elke Schonherr, Uwe Hansen, Renato V Iozzo, Horst Robenek, Peter Bruckner, Daniela G SeidlerAbstract:Decorin is a multifunctional small leucine-rich proteoglycan involved in the regulation of collagen fibrillogenesis. In patients with a variant of Ehlers–Danlos syndrome, about half of the secreted Decorin lacks the single glycosaminoglycan side chain. Notably, these patients have a skin-fragility phenotype that resembles that of Decorin null mice. In this study, we investigated the role of glycanated and unglycanated Decorin on collagen fibrillogenesis. Glycosaminoglycan-free Decorin, generated by mutating Ser4 of the mature protein core into Ala (DCN-S4A), showed reduced inhibition of fibrillogenesis compared with the Decorin proteoglycan. Interestingly, using a 3D matrix generated by Decorin-null fibroblasts, an increase in fibril diameter was found after the addition of Decorin, and even greater effects were observed with DCN-S4A. To avoid potential side effects of artificial tags, adenoviruses containing Decorin and DCN-S4A were used to transduce Decorin-null fibroblasts prior to matrix formation. Both molecules were efficiently incorporated into the matrix, with no changes in collagen composition and network formation, or altered expression of the related proteoglycan biglycan. Both Decorin and DCN-S4A mutants increased the collagen fibril diameter, with the latter showing the most prominent effects. These data show that at early stages of fibrillogenesis, the glycosaminoglycan chain of Decorin has a reducing effect on collagen fibril diameter.
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the glycosaminoglycan chain of Decorin plays an important role in collagen fibril formation at the early stages of fibrillogenesis
FEBS Journal, 2007Co-Authors: Claus Ruhland, Elke Schonherr, Uwe Hansen, Renato V Iozzo, Horst Robenek, Peter Bruckner, Daniela G SeidlerAbstract:Decorin is a multifunctional small leucine-rich proteoglycan involved in the regulation of collagen fibrillogenesis. In patients with a variant of Ehlers–Danlos syndrome, about half of the secreted Decorin lacks the single glycosaminoglycan side chain. Notably, these patients have a skin-fragility phenotype that resembles that of Decorin null mice. In this study, we investigated the role of glycanated and unglycanated Decorin on collagen fibrillogenesis. Glycosaminoglycan-free Decorin, generated by mutating Ser4 of the mature protein core into Ala (DCN-S4A), showed reduced inhibition of fibrillogenesis compared with the Decorin proteoglycan. Interestingly, using a 3D matrix generated by Decorin-null fibroblasts, an increase in fibril diameter was found after the addition of Decorin, and even greater effects were observed with DCN-S4A. To avoid potential side effects of artificial tags, adenoviruses containing Decorin and DCN-S4A were used to transduce Decorin-null fibroblasts prior to matrix formation. Both molecules were efficiently incorporated into the matrix, with no changes in collagen composition and network formation, or altered expression of the related proteoglycan biglycan. Both Decorin and DCN-S4A mutants increased the collagen fibril diameter, with the latter showing the most prominent effects. These data show that at early stages of fibrillogenesis, the glycosaminoglycan chain of Decorin has a reducing effect on collagen fibril diameter.
Rick T Owens - One of the best experts on this subject based on the ideXlab platform.
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the dermatan sulfate proteoglycan Decorin modulates α2β1 integrin and the vimentin intermediate filament system during collagen synthesis
PLOS ONE, 2012Co-Authors: Oliver Jungmann, Rick T Owens, Renato V Iozzo, Katerina Nikolovska, Christian Stock, Janniklas Schulz, Beate Eckes, Christoph Riethmuller, Daniela G SeidlerAbstract:Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of Decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn−/−) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn−/− mice could be rescued in vitro by Decorin but not with Decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn−/− fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of Decorin. We discovered that a Decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn−/− fibroblasts. This phenotype could be rescued by the Decorin proteoglycan but less efficiently by the Decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn−/− fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the Decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan Decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn−/−. Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that Decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn−/− phenotype.
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Decorin antagonizes the angiogenic network concurrent inhibition of met hypoxia inducible factor 1α vascular endothelial growth factor a and induction of thrombospondin 1 and timp3
Journal of Biological Chemistry, 2012Co-Authors: Thomas Neill, Rick T Owens, Liliana Schaefer, Hannah Painter, Simone Buraschi, Michael P Lisanti, Renato V IozzoAbstract:Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated Decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound Decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with Decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous Decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, Decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for Decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.
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Decorin is a novel antagonistic ligand of the Met receptor.
The Journal of cell biology, 2009Co-Authors: Silvia Goldoni, David J Mcquillan, Rick T Owens, Ashley C. Humphries, Alexander Nyström, Sampurna Sattar, Keith Ireton, Renato V IozzoAbstract:Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that Decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that Decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of Decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of Decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, Decorin contributes to reduction in primary tumor growth and metastastic spreading.
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genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by Decorin and biglycan
Journal of Biological Chemistry, 2009Co-Authors: Guiyun Zhang, David J Mcquillan, Silvia Goldoni, Rick T Owens, Renato V Iozzo, Shoujun Chen, Bennett W Calder, Holly C Simpson, Marian F Young, David E BirkAbstract:Abstract Decorin and biglycan are class I small leucine-rich proteoglycans (SLRPs) involved in regulation of collagen fibril and matrix assembly. We hypothesize that tissue-specific matrix assembly, such as in the cornea, requires a coordinate regulation involving multiple SLRPs. To this end, we investigated the expression of Decorin and biglycan in the cornea of mice deficient in either SLRP gene and in double-mutant mice. Decorin and biglycan exhibited overlapping spatial expression patterns throughout the corneal stroma with differential temporal expression. Whereas Decorin was expressed at relatively high levels in all developmental stages, biglycan expression was high early, decreased during development, and was present at very low levels in the mature cornea. Ultrastructural analyses demonstrated comparable fibril structure in the Decorin- and biglycan-null corneas compared with wild-type controls. We found a compensatory up-regulation of biglycan gene expression in the Decorin-deficient mice, but not the reverse. Notably, the corneas of compound Decorin/biglycan-null mice showed severe disruption in fibril structure and organization, especially affecting the posterior corneal regions, corroborating the idea that biglycan compensates for the loss of Decorin. Fibrillogenesis assays using recombinant Decorin and biglycan confirmed a functional compensation, with both having similar effects at high SLRP/collagen ratios. However, at low ratios Decorin was a more efficient regulator. The use of proteoglycan or protein core yielded comparable results. These findings provide firm genetic evidence for an interaction of Decorin and biglycan during corneal development and further suggest that Decorin has a primary role in regulating fibril assembly, a function that can be fine-tuned by biglycan during early development.
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A Central Role for Decorin during Vertebrate
2009Co-Authors: Jason J Zoeller, Wittaya Pimtong, Helen Corby, Silvia Goldoni, Alex E Iozzo, Rick T Owens, Renato V IozzoAbstract:Decorin, an archetypal member of the small leucine-rich pro- teoglycan gene family, regulates collagen fibrillogenesis and cell growth. To further explore its biological function, we examined the role of Decorin during zebrafish development. Zebrafish Decorin is a chondroitin sulfate proteoglycan that exhibits a high degree of conservation with its mammalian counterpart and displays a unique spatiotemporal expression pattern. Mor- pholino-mediated knockdown of zebrafish Decorin identified a developmental role during medial-lateral convergence and anterior-posterior extension of the body plan, as well as in craniofacial cartilage formation. Decorin morphants displayed a pronounced shortening of the head-to-tail axis as well as com- pression, flattening, and extension of the jaw cartilages. The morphant phenotype was efficiently rescued by zebrafish Decorin mRNA. Unexpectedly, microinjection of excess zebrafish Decorin mRNA or proteoglycan/protein core into one- cell stage embryos caused cyclopia. The morphant and overex- pression phenotype represent a convergent extension defect. Our results indicate a central function for Decorin during early embryogenesis.
David J Mcquillan - One of the best experts on this subject based on the ideXlab platform.
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Decorin is a novel antagonistic ligand of the Met receptor.
The Journal of cell biology, 2009Co-Authors: Silvia Goldoni, David J Mcquillan, Rick T Owens, Ashley C. Humphries, Alexander Nyström, Sampurna Sattar, Keith Ireton, Renato V IozzoAbstract:Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that Decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that Decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of Decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of Decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, Decorin contributes to reduction in primary tumor growth and metastastic spreading.
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genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by Decorin and biglycan
Journal of Biological Chemistry, 2009Co-Authors: Guiyun Zhang, David J Mcquillan, Silvia Goldoni, Rick T Owens, Renato V Iozzo, Shoujun Chen, Bennett W Calder, Holly C Simpson, Marian F Young, David E BirkAbstract:Abstract Decorin and biglycan are class I small leucine-rich proteoglycans (SLRPs) involved in regulation of collagen fibril and matrix assembly. We hypothesize that tissue-specific matrix assembly, such as in the cornea, requires a coordinate regulation involving multiple SLRPs. To this end, we investigated the expression of Decorin and biglycan in the cornea of mice deficient in either SLRP gene and in double-mutant mice. Decorin and biglycan exhibited overlapping spatial expression patterns throughout the corneal stroma with differential temporal expression. Whereas Decorin was expressed at relatively high levels in all developmental stages, biglycan expression was high early, decreased during development, and was present at very low levels in the mature cornea. Ultrastructural analyses demonstrated comparable fibril structure in the Decorin- and biglycan-null corneas compared with wild-type controls. We found a compensatory up-regulation of biglycan gene expression in the Decorin-deficient mice, but not the reverse. Notably, the corneas of compound Decorin/biglycan-null mice showed severe disruption in fibril structure and organization, especially affecting the posterior corneal regions, corroborating the idea that biglycan compensates for the loss of Decorin. Fibrillogenesis assays using recombinant Decorin and biglycan confirmed a functional compensation, with both having similar effects at high SLRP/collagen ratios. However, at low ratios Decorin was a more efficient regulator. The use of proteoglycan or protein core yielded comparable results. These findings provide firm genetic evidence for an interaction of Decorin and biglycan during corneal development and further suggest that Decorin has a primary role in regulating fibril assembly, a function that can be fine-tuned by biglycan during early development.
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An Antimetastatic Role for Decorin in Breast Cancer
The American journal of pathology, 2008Co-Authors: Silvia Goldoni, David J Mcquillan, Daniela G Seidler, Rick T Owens, Jack Heath, Matteo Fassan, Raffaele Baffa, Mathew L. Thakur, Renato V IozzoAbstract:Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We investigated the effects of Decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in comparison with AG879, an established ErbB2 kinase inhibitor. Cell proliferation and anchorage-independent growth assays showed that Decorin was a potent inhibitor of breast cancer cell growth and a pro-apoptotic agent. When Decorin and AG879 were used in combination, the inhibitory effect was synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active recombinant human Decorin protein core, AG879, or a combination of both was administered systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and metabolism were reduced by approximately 50% by both Decorin and AG879. However, no synergism was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of ErbB2 levels in the tumor xenografts. Most importantly, systemic delivery of Decorin prevented metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative assays. In contrast, AG879 failed to have any effect. Our data support a role for Decorin as a powerful and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth and metastatic spreading.
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Decorin modulates fibrin assembly and structure.
The Journal of biological chemistry, 2006Co-Authors: Tracey A. Dugan, David J Mcquillan, Vivian W.-c. Yang, Magnus HookAbstract:Next Section Abstract Emerging evidence indicates that fibrin clotting is regulated by different external factors. We demonstrated recently that Decorin, a regulator of collagen fibrillogenesis and transforming growth factor-β activity, binds to the D regions of fibrinogen (Dugan, T.A., Yang, V. W.-C., McQuillan, D.J., and Hook, M. (2003) J. Biol. Chem. 278, 13655–13662). We now report that the Decorin-fibrinogen interaction alters the assembly, structure, and clearance of fibrin fibers. Relative to fibrinogen, substoichiometric amounts of Decorin core protein modulated clotting, whereas an excess of an active Decorin peptide was necessary for similar activity. These concentration-dependent effects suggest that Decorin bound to the D regions sterically modulates fibrin assembly. Scanning electron microscopy images of fibrin clotted in the presence of increasing concentrations of Decorin core protein showed progressively decreasing fiber diameter. The sequestration of Zn2+ ions from the N-terminal fibrinogen-binding region abrogated Decorin incorporation into the fibrin network. Compared with linear thicker fibrin fibers, the curving thin fibers formed with Decorin underwent accelerated tissue-type plasminogen activator-dependent fibrinolysis. Collectively, these data demonstrate that Decorin can regulate fibrin organization and reveal a novel mechanism by which extracellular matrix components can participate in hemostasis, thrombosis, and wound repair.
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Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase 3 activation
Journal of Biological Chemistry, 2006Co-Authors: Daniela G Seidler, David J Mcquillan, Silvia Goldoni, Rick T Owens, Mathew L. Thakur, Christopher R Agnew, Christopher Cardi, Renato V IozzoAbstract:Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of Decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or Decorin protein core (2.5-10 mg kg-1) every 2 days for 18-38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by Decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant down-regulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of Decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, Decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby Decorin might influence cell growth and survival.
Liliana Schaefer - One of the best experts on this subject based on the ideXlab platform.
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Decorin as a multivalent therapeutic agent against cancer
Advanced drug delivery reviews, 2015Co-Authors: Thomas Neill, Liliana Schaefer, Renato V IozzoAbstract:Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble Decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, Decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, Decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, Decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, Decorin would be an ideal therapeutic candidate for combating solid malignancies.
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Decorin antagonizes the angiogenic network concurrent inhibition of met hypoxia inducible factor 1α vascular endothelial growth factor a and induction of thrombospondin 1 and timp3
Journal of Biological Chemistry, 2012Co-Authors: Thomas Neill, Rick T Owens, Liliana Schaefer, Hannah Painter, Simone Buraschi, Michael P Lisanti, Renato V IozzoAbstract:Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated Decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound Decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with Decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous Decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, Decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for Decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.
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Decorin a novel player in the insulin like growth factor system
Journal of Biological Chemistry, 2005Co-Authors: Elke Schonherr, Renato V Iozzo, Cord Sunderkotter, Liliana SchaeferAbstract:Decorin is a multifunctional proteoglycan that is expressed by sprouting endothelial cells. Its expression supports capillary formation and cell survival. Previously, it was shown that some effects of Decorin are mediated by protein kinase B and the cyclin-dependent kinase inhibitor, p21. However, the cell surface receptor responsible for these effects was unknown. We demonstrate that Decorin binds to the insulin-like growth factor-I (IGF-I) receptor on endothelial cells with an affinity in the nanomolar range (K(D) = 18 nm), which is comparable with IGF-I (K(D) = 1.2 nm). Furthermore, Decorin can bind IGF-I itself, but with a lower affinity (K(D) = 190 nm) than classical IGF-I-binding proteins. Decorin addition causes IGF-I receptor phosphorylation and activation, which is followed by receptor down-regulation. These effects are caused by the core protein of Decorin, and the binding region could be mapped to the N terminus of the molecule. The physiological relevance of the Decorin/IGF-I receptor interaction was corroborated in two animal models (e.g. inflammatory angiogenesis in the cornea and unilateral ureteral obstruction). In both models the IGF-I receptor was up-regulated in Decorin-deficient mice compared with controls and the up-regulation could not compensate the Decorin deficiency in the disease models. These data indicate that Decorin is an important player in the IGF system and its loss cannot fully be compensated in different types of diseases.
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In vivo selective and distant killing of cancer cells using adenovirus-mediated Decorin gene transfer
FASEB Journal, 2003Co-Authors: José Guilherme Tralhão, Elke Schonherr, Renato V Iozzo, Liliana Schaefer, Miroslava Micegova, César Evaristo, Samer Kayal, Henrique Veiga-fernandes, Claire Danel, Hans KresseAbstract:Decorin is a well-known, ubiquitous proteoglycan that is a normal component of the ECM. Upon transgenic expression of Decorin, tumor cells with diverse histogenetic background overexpress p21WAF1, a potent inhibitor of cyclin-dependent kinase activity, become arrested in G1, and fail to generate tumors in immunocompromised animals. Because Decorin is a secreted protein, it has been recently suggested that Decorin could act as an autocrine and paracrine regulator of tumor growth. Here, we demonstrate that adenovirus (Ad)-mediated transfer and expression of human Decorin cDNA induced in vivo apoptosis of xenograft tumor cells in nude mice. This oncolytic activity was observed when the Ad vector encoding the Decorin cDNA was injected intratumorally (i.t.) or i.v. Importantly, i.t. injection of the Decorin Ad vector led to growth inhibition of the injected tumor associated with similar growth inhibition of a distant contralateral tumor, demonstrating a distant Decorin antitumoral effect. Immunochemistry against human Decorin and Decorin quantitation in tumors confirmed that Decorin migrated to the tumor distant site. Furthermore, Decorin effect was specific to tumor cells, because neither apoptosis nor growth inhibition were observed in nontumoral human cells such as hepatocytes, endothelial cells, and fibroblasts, despite p21 overexpression.
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Decorin mediated signal transduction in endothelial cells involvement of akt protein kinase b in up regulation of p21waf1 cip1 but not p27kip1
Journal of Biological Chemistry, 2001Co-Authors: Elke Schonherr, Liliana Schaefer, Hans Kresse, Bodo Levkau, Kenneth WalshAbstract:Endothelial cells undergoing angiogenesis express Decorin, a small multifunctional proteoglycan. We have shown that Decorin is causally involved in the formation of capillary-like structures and a decrease in apoptosis in endothelial cells cultured in a collagen lattice. Here we investigate signal transduction pathways mediating the effects of Decorin. Reverse transcription-polymerase chain reaction demonstrated that p21 and p27, two inhibitors of cyclin-dependent kinases, were up-regulated by Decorin induction. Decorin also increased protein levels of p21 and caused its translocation into the nucleus. p21 synthesis started 6 h after Decorin addition and reached a plateau after 18 h, while cyclin A, which was also induced, peaked at 12 h and declined below basal levels within 24 h. These effects were mediated by the Akt/protein kinase B pathway. Akt phosphorylation at Thr-308 increased 4-fold and at Ser-473 1.4-fold within 10 min after Decorin addition. Overexpression of dominant negative Akt inhibited the Decorin-mediated induction of p21 and cyclin A, but had no effect on p27. These results show that Decorin is a signaling molecule in sprouting endothelial cells where it acts via different pathways, one of them involving Akt/protein kinase B.
