Interaction of the NG2 chondroitin sulfate proteoglycan with type VI collagen.

Stallcup, William B.; Dahlin, K J; Healy, Patricia A.

doi:10.1083/jcb.111.6.3177

Cited by 167 publications

(127 citation statements)

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“…Expression of mutant forms of NG2 that lack the collagen-binding domain (Burg et al, 1997;Tillet et al, 1997) does not produce this enhanced response to type VI collagen, thus allowing us to define a component of cell motility that is dependent on the interaction of NG2 with the collagen. The specificity of NG2/type VI collagen binding was previously established in several types of in vitro assays (Stallcup et al, 1990;Nishiyama and Stallcup, 1993;Burg et al, 1996), suggesting that NG2 could provide a mechanism for cellular interaction with the ECM. The motility studies show that this interaction is functionally important and indicate that binding of type VI collagen to NG2 triggers signaling mechanisms that lead to enhanced cell migration.…”

Section: Discussionmentioning

confidence: 86%

“…As a membrane-spanning molecule, NG2 is in a position to mediate communication between the extracellular and intracellular compartments of the cell. We have presented evidence that the ectodomain of NG2 may interact with several types of extracellular matrix (ECM) ligands (Burg et al, 1996), the best studied of which is type VI collagen (Stallcup et al, 1990;Nishiyama and Stallcup, 1993;Burg et al, 1996Burg et al, , 1997Tillet et al, 1997). These studies show that the central nonglobular segment of the NG2 ectodomain contains a binding site for type VI collagen, which allows the proteoglycan to serve as an efficient cell surface receptor for this ECM component.…”

Section: Introductionmentioning

confidence: 99%

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Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Fang

Burg

Barritt

et al. 1999

MBoC

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Cells expressing the NG2 proteoglycan can attach, spread, and migrate on surfaces coated with NG2 mAbs, demonstrating that engagement of NG2 can trigger the cytoskeletal rearrangements necessary for changes in cell morphology and motility. Engagement of different epitopes of the proteoglycan results in distinct forms of actin reorganization. On mAb D120, the cells contain radial actin spikes characteristic of filopodial extension, whereas on mAb N143, the cells contain cortical actin bundles characteristic of lamellipodia. Cells that express NG2 variants lacking the transmembrane and cytoplasmic domains are unable to spread or migrate on NG2 mAb-coated surfaces, indicating that these portions of the molecule are essential for NG2-mediated signal transduction. Cells expressing an NG2 variant lacking the C-terminal half of the cytoplasmic domain can still spread normally on mAbs D120 and N143, suggesting that the membraneproximal cytoplasmic segment is responsible for this process. In contrast, this variant migrates poorly on mAb D120 and exhibits abnormal arrays of radial actin filaments decorated with fascin during spreading on this mAb. The C-terminal portion of the NG2 cytoplasmic domain, therefore, may be involved in regulating molecular events that are crucial for cell motility.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Fang

Burg

Barritt

et al. 1999

MBoC

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“…The cell surface-associated membrane chondroitin sulfate proteoglycan NG2 was originally detected in cells from the rodent central nervous system but subsequently was also detected in blood vessels and cartilaginous structures of the head, neck, and spine. It interacts via its core protein with type VI collagen and is thought to provide machinery for transmembrane signaling (5). Since ␣1␤1 and ␣2␤1 integrins also bind type VI collagen (6,7), the cell signaling potential of this molecule would appear to be significant.…”

mentioning

confidence: 99%

Type VI Collagen Anchors Endothelial Basement Membranes by Interacting with Type IV Collagen

Kuo

Maslen

Keene

et al. 1997

Journal of Biological Chemistry

299

215

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Type VI collagen filaments are found associated with interstitial collagen fibers, around cells, and in contact with endothelial basement membranes. To identify type VI collagen binding proteins, the amino-terminal domains of the ␣1(VI) and ␣2(VI) chains and a part of the carboxyl-terminal domain of the ␣3(VI) chain were used as bait in a yeast two-hybrid system to screen a human placenta library. Eight persistently positive clones were identified, two coding the known matrix proteins fibronectin and basement membrane type IV collagen and the rest coding new proteins. The amino-terminal domain of ␣1(VI) was shown to interact with the carboxylterminal globular domain of type IV collagen. The specificity of this interaction was further studied using the yeast two-hybrid system in a one-on-one format and confirmed by using isolated protein domains in immunoprecipitation, affinity blots, and enzyme-linked immunosorbent assay-based binding studies. Co-distribution of type VI and type IV collagens in human muscle was demonstrated using double labeling immunofluorescent microscopy and immunoelectron microscopy. The strong interaction of type VI collagen filaments with basement membrane collagen provided a possible molecular pathogenesis for the heritable disorder Bethlem myopathy.Type VI collagen filaments are ubiquitous. They are present in all connective tissues that contain type I and type III collagen fibers and in cartilage, a tissue that contains predominantly type II collagen. The major functions that have been suggested for type VI collagen filamentous networks are as a substrate for cell attachment and as an anchoring meshwork that connects collagen fibers, nerves, and blood vessels to the surrounding matrix (1, 2). This implies that not only is there an interaction, either direct or indirect, with the type I/III collagen fibers but also that there is an interaction with components of endothelial basement membranes.Matrix components that have been shown to interact with type VI collagen in vitro include proteoglycans, collagens, hyaluronan, heparin, and integrins.Proteoglycans appear to be particularly important, since cell surface-, basement membrane-, and collagen fibril-associated proteoglycans have all been reported to bind to various forms of type VI collagen. Decorin is a small dermatan sulfate proteoglycan that binds to fibrillar collagens (3). It was shown that the leucine-rich module of the core protein bound to type VI and that the binding could be inhibited by the core proteins of fibromodulin and biglycan (4). The cell surface-associated membrane chondroitin sulfate proteoglycan NG2 was originally detected in cells from the rodent central nervous system but subsequently was also detected in blood vessels and cartilaginous structures of the head, neck, and spine. It interacts via its core protein with type VI collagen and is thought to provide machinery for transmembrane signaling (5). Since ␣1␤1 and ␣2␤1 integrins also bind type VI collagen (6, 7), the cell signaling potential of this molecule woul...

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“…61 These investigators also found that incubation with NG2 diminished the ability of angiostatin to inhibit endothelial cell proliferation, similar to our results with LBP in the rat aortic ring assays. NG2, like shed LBP, binds to the extracellular matrix 64 , such that both molecules can remain in the vicinity of a malignant tumor and may act as local positive modifiers of neoangiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tumor shedding of laminin binding protein modulates angiostatin production in vitro and interferes with plasmin‐derived inhibition of angiogenesis in aortic ring cultures

Moss

Taubner

Sample

et al. 2006

Intl Journal of Cancer

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The growth of solid tumors is largely controlled by the process of angiogenesis. A 67 kDa protein, the laminin binding protein (LBP), is shed from malignant cells in significant amounts and binds to laminin-1 (Starkey et al., Cytometry 1999;35:37-47; Karpatova et al., J Cell Biochem 1996;60:226-34). However, the functions of shed LBP are not fully understood. We hypothesize that matrix-bound LBP could modulate local tumor angiogenesis. In support of this hypothesis, we demonstrate that shed LBP exhibits sulfhydryl oxidase-like activities, and modifies the production of angiostatins from plasmin in vitro. The molecular weights of the autocatalytic products of lys-plasmin incubated with LBP in vitro suggest that PMDs (plasmin A chains attached to degraded B chains) (Ohyama et al., Eur J Biochem 2004;271: 809-20) are preferentially generated. Using rat aortic ring assays, we also show that shed LBP reverses plasmin-dependent inhibition of vascular outgrowth. To elucidate which LBP region(s) are active in modulating angiogenesis, limited proteolysis experiments were conducted to determine stable rLBP domains likely to fold correctly, and these were cloned, expressed and purified. The stable LBP fragments were tested for binding to laminin-1 and for competition with shed LBP activity in the aortic ring assay. Results of these studies suggest that the active LBP domains lie within the 137-230 amino acid sequence, a region known to contain 2 bioactive sequences. Since this fragment binds to laminin-1 and modulates angiogenesis, it appears likely that binding of shed LBP to matrix laminin-1 is related to its functions in tumor angiogenesis. The findings presented in this manuscript suggest that LBP shedding could provide a useful therapeutic target. ' 2005 Wiley-Liss, Inc.Key words: laminin binding protein; angiogenesis; angiostatin; limited proteolysisInitially isolated from tumor cell membrane extracts, overexpression of the 67 kDa laminin binding protein (LBP) is strongly correlated with metastatic and aggressive tumor cell phenotypes. [1][2][3][4][5][6][7][8] Furthermore, recent microarray expression profiling and proteomic studies have confirmed this established correlation, for instance see Refs. 9 and 10. Tumor angiogenesis is an important component of malignant behavior, and high expression of the LBP is associated with both pathological and normal neovascularization processes. 11,12 The 67 kDa form of the LBP is shed from tumor cells and binds to laminin-1 in the substrate matrix. 13,14 Neither the mechanism of this shedding nor the function of the shed protein is known, although it is likely that this process promotes laminin degradation and cell migration. 15 Induced conformational changes in laminin-1 follow binding of the 67 kDa LBP to this disulphide rich macromolecule, and these changes facilitate laminin degradation and promote overall tumor cell aggression. 16,17 Pathological tumor associated angiogenesis is a key component allowing continued cancer growth and facilitating metastasis. Under nonpathol...

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Interaction of the NG2 chondroitin sulfate proteoglycan with type VI collagen.

Cited by 167 publications

References 58 publications

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Type VI Collagen Anchors Endothelial Basement Membranes by Interacting with Type IV Collagen

Tumor shedding of laminin binding protein modulates angiostatin production in vitro and interferes with plasmin‐derived inhibition of angiogenesis in aortic ring cultures

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