Thrombospondin-4 Binds Specifically to Both Collagenous and Non-collagenous Extracellular Matrix Proteins via Its C-terminal Domains

Narouz-Ott, Laila; Maurer, Patrik; Nitsche, D. Patric; Smyth, Neil; Paulsson, Mats

doi:10.1074/jbc.m007223200

Cited by 86 publications

(77 citation statements)

References 33 publications

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“…Thrombospondins 3 and 4 have a pentameric conformation and are likely to have similar effects. It has been shown that thrombospondin 4 binds collagen in a zinc-dependent manner similar to COMP (37). With regard to thrombospondins 1 and 2, it is not clear whether their trimeric nature with fewer binding sites will result in a different effect on collagen fibrillogenesis.…”

Section: Discussionmentioning

confidence: 95%

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COMP Acts as a Catalyst in Collagen Fibrillogenesis

Halász

Kassner²,

Mörgelin

et al. 2007

Journal of Biological Chemistry

265

220

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We have previously reported that COMP (cartilage oligomeric matrix protein) is prominent in cartilage but is also present in tendon and binds to collagens I and II with high affinity. Here we show that COMP influences the fibril formation of these collagens. Fibril formation in the presence of pentameric COMP was much faster, and the amount of collagen in fibrillar form was markedly increased. Monomeric COMP, lacking the N-terminal coiled-coil linker domain, decelerated fibrillogenesis. The data show that stimulation of collagen fibrillogenesis depends on the pentameric nature of COMP and not only on collagen binding. COMP interacts primarily with free collagen I and II molecules, bringing several molecules to close proximity, apparently promoting further assembly. These assemblies further join in discrete steps to a narrow distribution of completed fibril diameters of 149 ؎ 16 nm with a banding pattern of 67 nm. COMP is not found associated with the mature fibril and dissociates from the collagen molecules or their early assemblies. However, a few COMP molecules are found bound to more loosely associated molecules at the tip/end of the growing fibril. Thus, COMP appears to catalyze the fibril formation by promoting early association of collagen molecules leading to increased rate of fibrillogenesis and more distinct organization of the fibrils.

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Section: Discussionmentioning

confidence: 95%

“…Similarly, other members of the TSP family show zinc ion-dependent interaction with fibrillar collagens. TSP 4, present in tendon, is found to interact via its C-terminal globules with collagens I, II, and III, with a K D of 4 -40 nM (37). TSP 1, present in cartilage, binds to collagen I in a similar manner as COMP.…”

mentioning

confidence: 92%

COMP Acts as a Catalyst in Collagen Fibrillogenesis

Halász

Kassner²,

Mörgelin

et al. 2007

Journal of Biological Chemistry

265

220

View full text Add to dashboard Cite

show abstract

“…42 Other proposed functions include a supportive role in myoblast adhesion 44 and interactions with other extracellular matrix proteins, such as certain collagens, laminin a 1, fibronectin and matrilin 2. 45 Given this information, hypothetical functions of THBS4 in the scenario of diffuse-type gastric cancer could include stimulation of proliferation of tumor cells or of other cell types and a facilitation of migratory behavior of tumor cells that elevates the invasive potential of the tumor.…”

Section: Thbs4 Expression In Gastric Adenocarcinomamentioning

confidence: 99%

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

et al. 2011

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Gastric adenocarcinomas can be divided into two major histological types, the diffuse and intestinal type (Laurén classification). Since they diverge in many clinical and molecular characteristics, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches. Gene expression profiling studies have identified numerous genes that are differentially expressed between them. However, none of these studies covered the whole transcriptome and the published gene lists reveal little overlap, raising the need for further, more comprehensive analyses. Here, we present the first transcriptome-wide expression profiling study comparing the two types (diffuse n ¼ 19, intestinal n ¼ 24), which identified 41000 genes that are differentially expressed. Among them, thrombospondin 4 (THBS4) showed the strongest correlation to histological type, with vast overexpression in the diffuse type. Quantitative real-time PCR validated this strong overexpression and revealed that intestinal tumors generally lack THBS4 expression. Immunohistochemistry demonstrated THBS4 overexpression on the protein level (n ¼ 10) and localized THBS4 to the stromal aspect. Its expression was primarily observed within the extracellular matrix surrounding the tumor cells, with the highest intensities found in regions of high tumor cell density and invasion. Intestinal tumors and matched non-neoplastic gastric epithelium and stroma did not feature any relevant THBS4 expression in a preliminary selection of analyzed cases (n ¼ 5). Immunohistochemical colocalization and in vitro studies revealed that THBS4 is expressed and secreted by cancer-associated fibroblasts. Furthermore, we show that THBS4 transcription in fibroblasts is stimulated by tumor cells. This study is the first to identify THBS4 as a powerful marker for diffuse-type gastric adenocarcinomas and to provide an initial characterization of its expression in the course of this disease.

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“…Thrombospondin 4 polymorphisms are associated with cardiovascular disease in epidemiological studies, [32][33][34] and there are some indications that it might act as an "adaptor protein in ECM assembly." 35,36 More studies on this interesting protein will be needed to investigate whether it might indeed be involved in the pathophysiology of aortic dissection.…”

Section: Nox1 and Angiotensin Ii-dependent Regulation Of Gene Expressionmentioning

confidence: 99%

NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II

et al. 2007

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Abstract-Oxidative stress leads to vascular damage and participates in the pathomechanisms of aortic dissection and aneurysm formation. Here we study aortic dissection in mice deficient in the superoxide-generating reduced nicotinamide-adenine dinucleotide phosphate oxidase NOX1. Seven days of treatment with the hypertensive agent angiotensin II (3 mg/kg per day) led to aortic dissection in 23% of wild-type C57BL/6J mice but in only 4% of NOX1-deficient mice (Pϭ0.05). In contrast, treatment of wild-type C57BL/6J mice with the hypertensive agent norepinephrine (12 mg/kg per day), did not lead to aortic dissection or sudden death, suggesting that hypertension is not sufficient to cause aortic dissection. Interestingly, norepinephrine-dependent blood pressure elevations were conserved in NOX1-deficient mice, demonstrating that, different from angiotensin II, it acts through NOX1-independent hypertensive mechanisms. The resistance of NOX1-deficient mice to angiotensin II-induced aortic dissection suggests a role for NOX1-dependent alterations of the vascular wall. We, therefore, studied gene expression and protease/inhibitor equilibrium. cDNA array analysis demonstrated differential effects of angiotensin II on gene expression in wild-type and NOX1-deficient mice. Tissue inhibitor of metalloproteinase 1 was increased both on the mRNA and the protein level in aortas from NOX1-deficient mice. Thus, our results demonstrate that NOX1 is involved in the mechanisms of angiotensin II-dependent aortic dissection. As one underlying mechanism, we have identified NOX1-dependent suppression of tissue inhibitor of metalloproteinase 1 expression, which could lead to tissue damage through an altered protease/inhibitor balance. Key Words: NOX1 Ⅲ nicotinamide-adenine dinucleotide phosphate oxidase Ⅲ blood pressure Ⅲ aortic dissection Ⅲ angiotensin II A ortic dissections and formation of aneurysms are serious and frequent medical conditions that are the consequence of damage to the vascular wall. Animals model play a key role in understanding their pathomechanisms. 1 Angiotensin II perfusion in mice has become a particularly valuable model for this pathological process. 2-5 Angiotensin II-induced vascular alterations include the following: (1) sustained blood pressure elevations; (2) increase in the thickness of the aortic media through mechanisms including smooth muscle hyperplasia, smooth muscle proliferation, and accumulation of extracellular matrix (ECM) proteins; (3) markers of inflammation, including oxidative damage to the vascular tissue, infiltration of monocytes/macrophages, and activation of matrix metalloproteinases; and (4) formation of aortic dissection and aneurysms. 1,4 Angiotensin II-dependent signal transduction is complex and involves Ն2 different receptors and the activation of multiple intracellular signaling pathways. 6,7 There is now increasing evidence that reactive oxygen species (ROS) are an important part of angiotensin II-dependent signal transduction 8 -12 involved in the pathogenesis of aortic aneurysms...

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Thrombospondin-4 Binds Specifically to Both Collagenous and Non-collagenous Extracellular Matrix Proteins via Its C-terminal Domains

Cited by 86 publications

References 33 publications

COMP Acts as a Catalyst in Collagen Fibrillogenesis

COMP Acts as a Catalyst in Collagen Fibrillogenesis

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II

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