Novel interactions of perlecan: Unraveling perlecan's role in angiogenesis

Bix, Gregory; Iozzo, Renato V.

doi:10.1002/jemt.20562

Cited by 91 publications

(64 citation statements)

References 134 publications

(124 reference statements)

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“…Besides integrins and heparan sulfate, it binds to an endogenous inhibitor of angiogenesis, endorepellin, a C-terminal domain of perlecan (37). Heparan sulfate proteoglycan-2 or perlecan, which plays a dual role in angiogenesis (38), also interacts with endostatin. Transglutaminase-2 is a new interacting partner of endostatin that is also involved in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The First Draft of the Endostatin Interaction Network

Faye

Chautard

Olsen

et al. 2009

Journal of Biological Chemistry

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Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It binds to heparin/heparan sulfate and to a number of proteins, but its molecular mechanisms of action are not fully elucidated. We have used surface plasmon resonance (SPR) arrays to identify new partners of endostatin, and to give further insights on its molecular mechanism of action. New partners of endostatin include glycosaminoglycans (chondroitin and dermatan sulfate), matricellular proteins (thrombospondin-1 and SPARC), collagens (I, IV, and VI), the amyloid peptide A␤-(1-42), and transglutaminase-2. The biological functions of the endostatin network involve a number of extracellular proteins containing epidermal growth factor and epidermal growth factor-like domains, and able to bind calcium. Depending on the trigger event, and on the availability of its members in a given tissue at a given time, the endostatin network might be involved either in the control of angiogenesis, and tumor growth, or in neurogenesis and neurodegenerative diseases.Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It inhibits angiogenesis and tumor growth (1-3). The effect of endostatin depends on its concentration (4, 5), on the length of exposure (6), on the type of endothelial cells (7), and on the growth factor inducing cell proliferation (fibroblast growth factor 2 or VEGF) 3 (8, 9). Endostatin binds to several membrane proteins including ␣5␤1 and ␣v␤3 integrins (10, 11), heparan sulfate proteoglycans (glypican-1 and -4) (12), and KDR/Flk1/VEGFR2 (13). We have previously characterized the binding of endostatin to heparan sulfate chains (9), and of endostatin to integrins (11). Furthermore, we have shown that ␣5␤1, ␣v␤3, and ␣v␤5 integrins bind to heparin/heparan sulfate (11).The broad molecular targets of endostatin suggest that multiple signaling systems are involved in mediation of its antiangiogenic action. Endostatin is a broad spectrum angiogenesis inhibitor that suppresses angiogenesis by blocking general mechanisms that govern endothelial cell growth (14), and initiates a complex network of signaling at the gene level (15). However, its molecular mechanism of action is still a matter of debate. An integrative view of the endostatin interaction network, including interactions between endostatin partners, is necessary to provide a clear understanding of how all these molecules work together to regulate angiogenesis, and tumor growth. This global approach places individual proteins into a functional context, and takes into account the fact that a single molecule such as endostatin can affect a wide range of other cell components. Indeed, most proteins and other components carry out their functions within a complex network of interactions and this approach based on protein-protein interaction networks has been developed for several years to give new clues on biological processes (16).This study ...

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Section: Discussionmentioning

confidence: 99%

The First Draft of the Endostatin Interaction Network

Faye

Chautard

Olsen

et al. 2009

Journal of Biological Chemistry

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“…Notably, the activity of SMI496 is reminiscent of that of endorepellin, a fragment of perlecan, which binds to the ␣2␤1 integrin and disrupts its function. 16,21 Lastly, endothelial cell migration on collagen was delayed by SMI496, even in the presence of a growth inhibitor. Thus, SMI496 inhibits endothelial cell collagen binding, migration on collagen, and collagen-induced capillary morphogenesis, but with little effect on proliferation.…”

Section: Discussionmentioning

confidence: 96%

A Key Role for the Integrin α2β1 in Experimental and Developmental Angiogenesis

Antonio

Zoeller

Habursky

et al. 2009

The American Journal of Pathology

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The ␣2␤1 integrin receptor plays a key role in angiogenesis. Here we investigated the effects of small molecule inhibitors (SMIs) designed to disrupt integrin ␣2 I or ␤1 I-like domain function on angiogenesis. In unchallenged endothelial cells, fibrillar collagen induced robust capillary morphogenesis. In contrast, tube formation was significantly reduced by SMI496, a ␤1 I-like domain inhibitor and by function-blocking anti-␣2␤1 but not -␣1␤1 antibodies. Endothelial cells bound fluorescein-labeled collagen I fibrils, an interaction specifically inhibited by SMI496. Moreover, SMI496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound healing. SMI activities were examined in vivo by supplementing the growth medium of zebrafish embryos expressing green fluorescent protein under the control of the vascular endothelial growth factor receptor-2 promoter. SMI496, but not a control compound, interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels. We further characterized zebrafish ␣2 integrin and discovered that this integrin is highly conserved, especially the I domain. Notably, a similar vascular phenotype was induced by morpholino-mediated knockdown of the integrin ␣2 subunit. By live videomicroscopy, we confirmed that the vessels were largely nonfunctional in the absence of ␣2␤1 integrin. Collectively , our results provide strong biochemical and genetic evidence of a central role for ␣2␤1 integrin in experimental and developmental angiogenesis.

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“…Although Perlecan has a proangiogenic role (43), its domain V, C-terminal fragment Endorepellin has potent antiangiogenic properties (44), providing it with a potential role in the development of a relatively avascular scar tissue that partially leads to progressive renal damage. Particularly, LG3 peptide can be generated from Endorepellin or Perlecan by a specific proteolytic cleavage carried out by bone morphogenetic protein-1/Toll-like family of metalloproteinases, ubiquitous enzymes that are involved in tissue remodeling and inflammation (45).…”

Section: Discussionmentioning

confidence: 99%

Association of Urinary Laminin G-Like 3 and Free K Light Chains with Disease Activity and Histological Injury in IgA Nephropathy

Rocchetti

Papale

d'Apollo

et al. 2013

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives IgA nephropathy has variable clinical presentation and progression. Its definitive diagnosis and prognosis require renal biopsy. The identification of new biomarkers allowing noninvasive diagnosis and monitoring of disease activity would be advantageous. This study analyzed the urine proteome of IgA nephropathy patients at an early stage of disease. Design, setting, participants, & measurements Urine from 49 IgA nephropathy patients, 42 CKD patients, and 40 healthy individuals was analyzed by surface-enhanced laser desorption/ionization time of flight/mass spectrometry. Differentially excreted proteins were identified by matrix-enhanced laser desorption/ionization time of flight/mass spectrometry, confirmed by immunologic methods, and validated in an independent set of patients (14 IgA nephropathy and 24 CKD). All patients were recruited at the Division of Nephrology of the University of Foggia from January of 2005 to March of 2007. Results Two proteins, with 21,598 and 23,458 m/z, were significantly decreased in IgA nephropathy and identified as Perlecan laminin G-like 3 peptide and Ig κ light chains, respectively. Western blot analysis confirmed the lower urinary excretion of laminin G-like 3 in IgA nephropathy patients compared with CKD patients and healthy individuals. Immunonephelometry analysis confirmed the lower urinary excretion of free κ light chains in IgA nephropathy patients compared with CKD patients and healthy individuals. Immunohistochemistry analysis justified the urinary excretion profile of such proteins in IgA nephropathy. Finally, urinary free κ light chains and laminin G-like 3 concentration inversely correlated with severity of clinical and histologic features of our IgA nephropathy cohort. Conclusions Laminin G-like 3 and free κ light chains can contribute to the noninvasive assessment of IgA nephropathy disease activity.

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Novel interactions of perlecan: Unraveling perlecan's role in angiogenesis

Cited by 91 publications

References 134 publications

The First Draft of the Endostatin Interaction Network

The First Draft of the Endostatin Interaction Network

A Key Role for the Integrin α2β1 in Experimental and Developmental Angiogenesis

Association of Urinary Laminin G-Like 3 and Free K Light Chains with Disease Activity and Histological Injury in IgA Nephropathy

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