Structural Basis for the Functions of Endogenous Angiogenesis Inhibitors

Grant, Marianne A.; Kalluri, Raghu

doi:10.1101/sqb.2005.70.017

Cited by 21 publications

(11 citation statements)

References 101 publications

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“…Endostatin is expressed by corneal and conjunctival epithelial cells and is essential in maintaining corneal avascularity and transparency (30). However, there has been no systematic study of endogenous endostatin regulation during immune-mediated graft rejection.…”

Section: Discussionmentioning

confidence: 99%

“…The constitutive presence of endostatin in corneas suggests that this molecule may play an important role in maintaining corneal avascularity and transparency. The current hypothesis surrounding endogenous endostatin activity is that, during endothelial activation, the production of proteolytic enzymes from BMs leads to a release of antiangiogenic fragments to serve as local inhibitors of angiogenesis (30). We hypothesize that endostatin is the "endogenous factor" that links angiogenesis to the immunological rejection of corneal allografts.…”

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confidence: 99%

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Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Tan

Cruz-Guilloty

Medina-Mendez

et al. 2012

The Journal of Immunology

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Corneal transplantation is the most common solid organ transplantation. The immunologically privileged nature of the cornea results in high success rates. However, T cell-mediated rejection is the most common cause of corneal graft failure. Using antiangiogenesis treatment to prevent corneal neovascularization, which revokes immune privilege, prevents corneal allograft rejection. Endostatin is an antiangiogenic factor that maintains corneal avascularity. In this study, we directly test the role of antiangiogenic and immunological signals in corneal allograft survival, specifically the potential correlation of endostatin production and T cell recruitment. We report that 75% of the corneal allografts of BALB/c mice rejected after postoperative day (POD) 20, whereas all syngeneic grafts survived through POD60. This correlates with endogenous endostatin, which increased and remained high in syngeneic grafts but decreased after POD10 in allografts. Immunostaining demonstrated that early recruitment of allospecific T cells into allografts around POD10 correlated with decreased endostatin production. In Rag−/− mice, both allogeneic and syngeneic corneal grafts survived; endostatin remained high throughout. However, after T cell transfer, the allografts eventually rejected, and endostatin decreased. Furthermore, exogenous endostatin treatment delayed allograft rejection and promoted survival secondary to angiogenesis inhibition. Our results suggest that endostatin plays an important role in corneal allograft survival by inhibiting neovascularization and that early recruitment of allospecific T cells into the grafts promotes destruction of endostatin-producing cells, resulting in corneal neovascularization, massive infiltration of effector T cells, and ultimately graft rejection. Therefore, combined antiangiogenesis and immune suppression will be more effective in maintaining corneal allograft survival.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Tan

Cruz-Guilloty

Medina-Mendez

et al. 2012

The Journal of Immunology

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“…Signaling from these molecules most probably involves binding or interference with specific integrins [1,9]. A third class of angiogenesis regulators comprises secreted enzymes, most of which are proangiogenic by facilitating endothelial cells migration through degradation of matrix macromolecules and promoting the release of pro-angiogenic cytokines and growth factors immobilized in the ECM.…”

Section: Introductionmentioning

confidence: 99%

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

Dubail¹,

Kesteloot²,

Deroanne³

et al. 2010

Cell. Mol. Life Sci.

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ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly reduced branching of capillarylike structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2.

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“…In humans, numerous diseases result from mutations in collagen genes [16]. In addition to structural roles, collagens interact with many cell membrane proteins, such as during cell adhesion to collagen in tissues, cell migration through collagen-rich stroma in normal differentiation and abnormal metastasis and in cell interactions in hemostasis [17,18]. Fewer interactions have been reported between leukocytes and collagen as might be expected given the requirement of leukocytes to respond to the invasion by pathogens such as bacteria and viruses.…”

Section: Introductionmentioning

confidence: 99%

New assay to detect low‐affinity interactions and characterization of leukocyte receptors for collagen including leukocyte‐associated Ig‐like receptor‐1 (LAIR‐1)

Jiang

Barclay

2009

Eur J Immunol

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Leukocyte activity is controlled by numerous interactions between membrane receptors and ligands on the cell surface. These interactions are of low affinity making detection difficult. We developed a sensitive assay that could readily detect extremely weak interactions such as that between CD200 and the activating receptor CD200RLa (K d 4500 lM) at the protein level. We used the new technology to screen for interactions of inhibitory receptors for collagens. We confirmed that both human and mouse leukocyte-associated Ig-like receptor-1, and in addition the related inhibitory leukocyte Ig-like receptor subfamily B member 4 (CD85K, Gp49B), bound collagen specifically, whereas other cell surface proteins gave no binding. The monomeric affinities of the interactions were then determined to allow comparison with other leukocyte interactions and indicate conditions when these interactions might lead to inhibitory signals.Key words: Collagen . Inhibitory receptor . Leukocyte-associated Ig-like receptor-1 (LAIR-1) . Surface interaction and immunoregulation IntroductionLeukocyte activity is controlled by the interactions of its surface proteins with both soluble factors such as cytokines and chemokines, and ligands on other cells. Thus identification of ligands is essential in understanding the role of the receptors in regulation. However, the interactions of cell surface proteins with other cell surfaces tend to be of very low affinity when determined using isolated recombinant proteins corresponding to the extracellular regions of the proteins. For instance, typical affinities for such interactions are around 2 mM (CTLA4/CD80 K d 5 2 mM, SIRPa/CD47 K d 5 2 mM, CD2/CD58 K d 5 10 mM, CD200/CD200R K d 5 2 mM) [1-6] with fast off rates usually giving half-lives of the order of 1 s. (discussed in [7]). These proteins, of various valencies, could be adapted and applied to screen for cells expressing receptors by flow cytometry and protein microarray [5,8,9]. With the ease of producing panels of recombinant proteins a powerful way of identifying new interactions is by screening at the protein level as illustrated by Eaton and co-workers using libraries of Fc fusion proteins [10].In the present study we developed a highly sensitive beadbinding assay capable of detecting exceptionally weak interactions using immobilized proteins and surface plasmon resonance (SPR). This is the combination of a conventional binding assay using SPR with the screening reagent -multivalent nanoparticles -taking advantage of the avidity of both reactants. Using the new assay we were able to examine the weak interaction between collagen and leukocyte membrane proteins. The recent identification of a motif in collagen as a ligand for the inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1) is intriguing as it Collagens are the most abundant proteins in the body with major roles in the extracellular matrix of mammalian cells, either as network-forming or fibrillar molecules. They are intimately involved in cell adhesion, migration and different...

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Structural Basis for the Functions of Endogenous Angiogenesis Inhibitors

Cited by 21 publications

References 101 publications

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

New assay to detect low‐affinity interactions and characterization of leukocyte receptors for collagen including leukocyte‐associated Ig‐like receptor‐1 (LAIR‐1)

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