Opticin Exerts Its Anti-angiogenic Activity by Regulating Extracellular Matrix Adhesiveness

Goff, Mhorag; Sutton, Matthew; Slevin, Mark; Latif, Ayşe; Humphries, Martin J.; Bishop, Paul N.

doi:10.1074/jbc.m111.331157

Cited by 37 publications

(30 citation statements)

References 48 publications

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“…The preparation of ECs and Matrigel TM was performed as described previously [18]. 6x10 3 cells were added to the Matrige TM reduced in growth factors (Becton Dickinson, UK; prepared according to the supplier’s instructions), in complete EBM-2 media with or without scalar amount of tested compound.…”

Section: Methodsmentioning

confidence: 99%

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Bosutti

Pennucci

et al. 2013

PLoS ONE

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Cyclin-dependent kinase-5 (Cdk5) is over-expressed in both neurons and microvessels in hypoxic regions of stroke tissue and has a significant pathological role following hyper-phosphorylation leading to calpain-induced cell death. Here, we have identified a critical role of Cdk5 in cytoskeleton/focal dynamics, wherein its activator, p35, redistributes along actin microfilaments of spreading cells co-localising with p(Tyr15)Cdk5, talin/integrin beta-1 at the lamellipodia in polarising cells. Cdk5 inhibition (roscovitine) resulted in actin-cytoskeleton disorganisation, prevention of protein co-localization and inhibition of movement. Cells expressing Cdk5 (D144N) kinase mutant, were unable to spread, migrate and form tube-like structures or sprouts, while Cdk5 wild-type over-expression showed enhanced motility and angiogenesis in vitro, which was maintained during hypoxia. Gene microarray studies demonstrated myocyte enhancer factor (MEF2C) as a substrate for Cdk5-mediated angiogenesis in vitro. MEF2C showed nuclear co-immunoprecipitation with Cdk5 and almost complete inhibition of differentiation and sprout formation following siRNA knock-down. In hypoxia, insertion of Cdk5/p25-inhibitory peptide (CIP) vector preserved and enhanced in vitro angiogenesis. These results demonstrate the existence of critical and complementary signalling pathways through Cdk5 and p35, and through which coordination is a required factor for successful angiogenesis in sustained hypoxic condition.

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Section: Methodsmentioning

confidence: 99%

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Bosutti

Pennucci

et al. 2013

PLoS ONE

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“…More recently, opticin was shown to be anti‐angiogenic and to inhibit preretinal neovascularization by modulating cell–ECM adhesion (Le Goff et al . ,b). Within cartilage, collagen fibrils interact with other ECM components to maintain and regulate tissue development, structural integrity and fibrillogenesis, and the absence or mutation of collagen type XI within cartilage leads to disease (Table ).…”

Section: Isolation and Analysis Of Ecmmentioning

confidence: 99%

Defining the extracellular matrix using proteomics

Byron

Humphries

2013

Int J Experimental Path

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SUMMARYThe cell microenvironment has a profound influence on the behaviour, growth and survival of cells. The extracellular matrix (ECM) provides not only mechanical and structural support to cells and tissues but also binds soluble ligands and transmembrane receptors to provide spatial coordination of signalling processes. The ability of cells to sense the chemical, mechanical and topographical features of the ECM enables them to integrate complex, multiparametric information into a coherent response to the surrounding microenvironment. Consequently, dysregulation or mutation of ECM components results in a broad range of pathological conditions. Characterization of the composition of ECM derived from various cells has begun to reveal insights into ECM structure and function, and mechanisms of disease. Proteomic methodologies permit the global analysis of subcellular systems, but extracellular and transmembrane proteins present analytical difficulties to proteomic strategies owing to the particular biochemical properties of these molecules. Here, we review advances in proteomic approaches that have been applied to furthering our understanding of the ECM microenvironment. We survey recent studies that have addressed challenges in the analysis of ECM and discuss major outcomes in the context of health and disease. In addition, we summarize efforts to progress towards a systems-level understanding of ECM biology.Keywords cell adhesion, extracellular matrix, mass spectrometry, proteomics Intercellular cohesion and communication are fundamental requirements of multicellular organisms. Indeed, the selective adhesion of cells to one another and to the extracellular matrix (ECM) within which they reside is necessary for much of metazoan anatomy and development ( € Ozbek et al. 2010; Hynes 2012). The ECM provides a structural framework for cell binding, and this enables tissues and organs to form. In addition, the composition and organization of the ECM play key roles in determining how cells interact with and respond to their microenvironment (Frantz et al. 2010). Thus, the ECM defines the physical and chemical interactions that control cellular physiology and fate.The identification and quantification of the components of distinct ECMs, the spatial and temporal dynamics of ECM molecules and the interactions underpinning ECM protein networks represent key steps towards understanding the role of the ECM in health and disease. Proteomics, the study of all proteins in a given system, offers an opportunity to address these challenges in a global manner, without the need for investigations based on predetermined molecular candidates. Here, we review recent progress in the isolation and proteomic analysis of extracellular molecules, with a focus on mass spectrometry (MS)-based proteomic strategies aimed at the non-specialist. A complete overview of ECM composition is beyond the scope of this review; rather, we highlight the technical and biological aspects of the latest ECM proteomic studies and discuss implications for futur...

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“…The extracellular matrix proteins decorin, biglycan and opticin, all of which are LRR proteins similar to chondro-adherin, are known to form homodimers (Le Goff et al, 2012;Scott et al, 2003Scott et al, , 2006. Indeed, dimerization in solution has been observed both for cartilage-tissue-extracted CHAD and for native and recombinantly expressed CHAD (Larsson et al, 1991;Må nsson et al, 2001;Pramhed et al, 2008).…”

Section: Hchad Forms a Dimer In The Crystalmentioning

confidence: 99%

Crystal structure of human chondroadherin: solving a difficult molecular-replacement problem usingde novomodels

Rämisch

Pramhed

Tillgren

et al. 2017

Acta Crystallogr D Struct Biol

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Chondroadherin (CHAD) is a cartilage matrix protein that mediates the adhesion of isolated chondrocytes. Its protein core is composed of 11 leucine-rich repeats (LRR) flanked by cysteine-rich domains. CHAD makes important interactions with collagen as well as with cell-surface heparin sulfate proteoglycans and αβ integrins. The integrin-binding site is located in a region of hitherto unknown structure at the C-terminal end of CHAD. Peptides based on the C-terminal human CHAD (hCHAD) sequence have shown therapeutic potential for treating osteoporosis. This article describes a still-unconventional structure solution by phasing with de novo models, the first of a β-rich protein. Structure determination of hCHAD using traditional, though nonsystematic, molecular replacement was unsuccessful in the hands of the authors, possibly owing to a combination of low sequence identity to other LRR proteins, four copies in the asymmetric unit and weak translational pseudosymmetry. However, it was possible to solve the structure by generating a large number of de novo models for the central LRR domain using Rosetta and multiple parallel molecular-replacement attempts using AMPLE. The hCHAD structure reveals an ordered C-terminal domain belonging to the LRRCT fold, with the integrin-binding motif (WLEAK) being part of a regular α-helix, and suggests ways in which experimental therapeutic peptides can be improved. The crystal structure itself and docking simulations further support that hCHAD dimers form in a similar manner to other matrix LRR proteins.

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Opticin Exerts Its Anti-angiogenic Activity by Regulating Extracellular Matrix Adhesiveness

Cited by 37 publications

References 48 publications

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia

Defining the extracellular matrix using proteomics

Crystal structure of human chondroadherin: solving a difficult molecular-replacement problem usingde novomodels

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