The Experts below are selected from a list of 5814 Experts worldwide ranked by ideXlab platform
David A. Cheresh - One of the best experts on this subject based on the ideXlab platform.
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Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Martin Friedlander, Chandra L. Theesfeld, Miyuki Sugita, Marcus Fruttiger, Matthew A. Thomas, Stanley Chang, David A. ChereshAbstract:Angiogenesis underlies the majority of eye diseases that result in catastrophic loss of vision. Recent evidence has implicated the integrins alpha v beta 3 and alpha v beta 5 in the angiogenic process. We examined the expression of alpha v beta 3 and alpha v beta 5 in neovascular ocular tissue from patients with subretinal neovascularization from age-related macular degeneration or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinopathy (PDR). Only alpha v beta 3 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular histoplasmosis, whereas both alpha v beta 3 and alpha v beta 5 were present on vascular cells in tissues from patients with PDR. Since we observed both integrins on vascular cells from tissues of patients with retinal neovascularization from PDR, we examined the effects of a systemically administered cyclic peptide antagonist of alpha v beta 3 and alpha v beta 5 on retinal angiogenesis in a murine model. This antagonist specifically blocked new blood vessel formation with no effect on established vessels. These results not only reinforce the concept that retinal and subretinal neovascular diseases are distinct pathological processes, but that antagonists of alpha v beta 3 and/or alpha v beta 5 may be effective in treating individuals with blinding eye disease associated with angiogenesis.
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Human neural cell adhesion molecule L1 and rat homologue NILE are ligands for integrin alpha v beta 3.
Journal of Cell Biology, 1996Co-Authors: Anthony M.p. Montgomery, David A. Cheresh, Jürgen C. Becker, Vance Lemmon, James D. Pancook, Xiaoning Zhao, Ralph A. ReisfeldAbstract:Integrin alpha v beta 3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. Here, we demonstrate that in addition to the recognition of ECM components, alpha v beta 3 can interact with the neural cell adhesion molecule L1-CAM; a member of the immunoglobulin superfamily (IgSF). M21 melanoma cells displayed significant Ca(++)-dependent adhesion and spreading on immunopurified rat L1 (NILE). This adhesion was found to be dependent on the expression of the alpha v-integrin subunit and could be significantly inhibited by an antibody to the alpha v beta 3 heterodimer. M21 cells also displayed some alpha v beta 3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and alpha v beta 3 was also observed to promote significant haptotactic cell migration. To map the site of alpha v beta 3 ligation we used recombinant L1 fragments comprising the entire extracellular domain of human L1. Significant alpha v beta 3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. We conclude that alpha v beta 3-dependent recognition of human L1 is dependent on ligation of this RGD site. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. In this regard, alpha v beta 3 may recognize L1 in a cell-cell or cell-substrate interaction.
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Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.
Journal of Clinical Investigation, 1995Co-Authors: Peter C. Brooks, Staffan Strömblad, Richard L. Klemke, Daniel W Visscher, F. H. Sarkar, David A. ChereshAbstract:Abstract Angiogenesis plays a fundamental role in human breast tumor progression. In fact, recent findings indicate that vascular density is a prognostic indicator of breast cancer disease status. Evidence is presented that the integrin alpha v beta 3 is not only a marker of human breast tumor-associated blood vessels, but that it plays a significant role in human angiogenesis and breast tumor growth. To assess the role of alpha v beta 3-dependent angiogenesis in the progression of human breast cancer, we examined a SCID mouse/human chimeric model with transplanted full thickness human skin containing alpha v beta 3-negative human breast tumor cells. This tumor induced a human angiogenic response as measured by vascular cell immunoreactivity with monoclonal antibodies LM609 and P2B1 directed to human alpha v beta 3 and CD31, respectively. Intravenous administration of LM609 either prevented tumor growth or markedly reduced tumor cell proliferation within the microenvironment of the human skin. These LM609-treated tumors not only contained significantly fewer human blood vessels but also appeared considerably less invasive than tumors in control animals. These findings demonstrate that alpha v beta 3 antagonists may provide an effective antiangiogenic approach for the treatment of human breast cancer.
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Engagement of the osteoclast integrin alpha v beta 3 by osteopontin stimulates phosphatidylinositol 3-hydroxyl kinase activity
Endocrinology, 1995Co-Authors: Keith A. Hruska, Felice Rolnick, Margaret Huskey, Ulises Alvarez, David A. ChereshAbstract:Osteoclast adhesion via integrin alpha v beta 3 to the bone matrix protein osteopontin (OPN) results in stimulation of bone resorption. We characterized an immediate signaling event that takes place upon osteoclast interaction with OPN. OPN binding to alpha v beta 3 results in the rapid production of the phosphoinositides (PtdInsP), including phosphatidylinositol triphosphate (PtdIns 3,4,5P3). Stimulation of 3,4,5-PtdInsP3 production by OPN was produced by increased activity of PtdInsP 3-OH kinase, which was found in immunoprecipitates formed by antibodies to integrin alpha v beta 3. The association of PtdIns 3-OH kinase with integrin may have been through association with c-src. The latter was present in immunoprecipitates formed by the antibodies to integrin alpha v beta 3, and src kinase was activated by OPN. These findings demonstrate a mechanism for rapid generation of cell signals upon matrix protein binding to alpha v beta 3, which resembles the mechanisms used by tyrosine kinase growth factor rece...
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The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro.
Journal of Clinical Investigation, 1995Co-Authors: Lucy Liaw, David A. Cheresh, Michael P. Skinner, Elaine W. Raines, Russell Ross, Stephen M. Schwartz, Cecilia M. GiachelliAbstract:Abstract Osteopontin is an arginine-glycine-aspartate containing acidic glycoprotein postulated to mediate adhesion, migration, and biomineralization in diverse tissues. The mechanisms explaining this multifunctionality are not well understood, although it is known that one osteopontin receptor is the alpha v beta 3 integrin. In this work, we studied human smooth muscle cells varying in alpha v beta 3 levels to identify additional osteopontin receptors. We report that, in addition to alpha v beta 3, both alpha v beta 5 and alpha v beta 1 are osteopontin receptors. Moreover, the presence or absence of alpha v beta 3 on the cell surface altered the adhesive and migratory responses of smooth muscle cells to osteopontin. Adhesion of alpha v beta 3-deficient cell populations to osteopontin was only half that of cells containing alpha v beta 3, and migration toward an osteopontin gradient in the Boyden chamber was dependent on cell surface alpha v beta 3. Although alpha v beta 3-deficient smooth muscle cells were unable to migrate to osteopontin, they did migrate significantly in response to vitronectin and fibronectin. These findings represent the first description of alpha v beta 5 and alpha v beta 1 as osteopontin receptors and suggest that, while adhesion to osteopontin is supported by integrins containing beta 1, beta 3, and beta 5, migration in response to osteopontin appears to depend on alpha v beta 3. Thus, interaction with distinct receptors is one mechanism by which osteopontin may initiate multiple functions.
Edmond Sabo - One of the best experts on this subject based on the ideXlab platform.
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‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin
Cell Death & Disease, 2016Co-Authors: Hanan Abu-tayeh, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Geula Klorin, Jeffrey E Green, Edmond SaboAbstract:Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int- α v β 3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int- α v β 3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids’ reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAM^highCD49f^lowCD24^+ and Int- α v β 3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int- α v β 3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int- α v β 3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int- α v β 3 can potentially promote ‘normalization’ of their malignant phenotype and may prevent the malignant cells from progressing.
Hanan Abu-tayeh - One of the best experts on this subject based on the ideXlab platform.
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'Normalizing' the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin.
Cell Death and Disease, 2016Co-Authors: Hanan Abu-tayeh, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Jeffrey Green, Geula KlorinAbstract:‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin
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‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin
Cell Death & Disease, 2016Co-Authors: Hanan Abu-tayeh, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Geula Klorin, Jeffrey E Green, Edmond SaboAbstract:Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int- α v β 3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int- α v β 3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids’ reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAM^highCD49f^lowCD24^+ and Int- α v β 3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int- α v β 3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int- α v β 3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int- α v β 3 can potentially promote ‘normalization’ of their malignant phenotype and may prevent the malignant cells from progressing.
B Baxt - One of the best experts on this subject based on the ideXlab platform.
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Analysis of foot-and-mouth disease virus integrin receptor expression in tissues from naïve and infected cattle.
Journal of comparative pathology, 2009Co-Authors: V O'donnell, J M Pacheco, D Gregg, B BaxtAbstract:Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals principally affecting cattle, pigs and sheep. FMD virus (FMDV) uses the alpha(V)beta(1), alpha(V)beta(3), alpha(V)beta(6), and alpha(V)beta(8) integrins as receptors in vitro via a highly conserved arginine-glycine-aspartic acid amino acid sequence motif located within the betaG-betaH loop of VP1. Immunofluorescence and confocal microscopy were used to study the expression of two major FMDV receptors, alpha(V)beta(3) and alpha(V)beta(6), within epithelial tissues from FMDV-infected and uninfected cattle in order to understand the role of these receptors in tissue tropism. Integrin alpha(V)beta(6) was expressed by epithelial cells in tissues that are important sites for FMDV replication (i.e. tongue and coronary band). Integrin alpha(V)beta(3) was detected in epithelium of all tissues examined except tongue. In addition, alpha(V)beta(3) expression was associated with blood vessels in all tissues examined. In infected tissues, alpha(V)beta(6) integrin was distributed on the surface of those epithelial cells also expressing FMDV antigen. Although integrin alpha(V)beta(3) has been shown to be a receptor for FMDV, no expression of alpha(V)beta(3) was associated with FMDV-positive keratinocytes in the tongue. In contrast, podal epithelial cells containing FMDV antigen also expressed alpha(V)beta(3) integrin. Thus, at the cellular level the expression of these two integrins correlates with susceptibility to infection and may contribute substantially to viral tropism in FMD pathogenesis.
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antibodies to the vitronectin receptor integrin alpha v beta 3 inhibit binding and infection of foot and mouth disease virus to cultured cells
Journal of Virology, 1995Co-Authors: A Berinstein, M Roivainen, T Hovi, P W Mason, B BaxtAbstract:The amino acid sequence Arg-Gly-Asp (RGD) is highly conserved on the VP1 proteins of different serotypes and subtypes of foot-and-mouth disease virus (FMDV) and is essential for cell attachment. This sequence is also found in certain extracellular matrix proteins that bind to a family of cell surface receptors called integrins. Within the Picornaviridae family, enterovirus coxsackievirus A9 also has an RGD motif on its VP1 capsid protein and has recently been shown to utilize the vitronectin receptor integrin alpha V beta 3 as a receptor on monkey kidney cells. Competition binding experiments between type A12 FMDV and coxsackievirus A9 using BHK-21 and LLC-MK2 cells revealed shared receptor specificity between these two viruses. Polyclonal anti-serum to the vitronectin receptor and a monoclonal antibody to the alpha V subunit inhibited both FMDV binding and plaque formation, while a monoclonal antibody to the beta 3 subunit inhibited virus binding. In contrast, antibodies to the fibronectin receptor (alpha 5 beta 1) or to the integrin (alpha V beta 5) had no effect on either binding or plaque formation. These data demonstrate that the alpha V beta 3 vitronectin receptor can function as a receptor for FMDV.
Israel F. Charo - One of the best experts on this subject based on the ideXlab platform.
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characterization of the integrin specificities of disintegrins isolated from american pit viper venoms
Journal of Biological Chemistry, 1993Co-Authors: Robert M Scarborough, Jack W Rose, M A Naughton, David R Phillips, L Nannizzi, Ann E Arfsten, A M Campbell, Israel F. CharoAbstract:Abstract A new series of homologous disintegrins was isolated from the venoms of new world pit viper genus Bothrops, Crotalus, and Lachesis. The relative activities of each disintegrin in blocking adhesive protein binding activities of GPIIb-IIIa, alpha v beta 3, and alpha 5 beta 1 were determined and correlated with their primary amino acid sequences. Four disintegrins contained the RGDW sequence and were found to be approximately twice as effective in blocking the binding of fibrinogen to GPIIb-IIIa than inhibiting the binding of vitronectin to alpha v beta 3 in solid-phase ligand binding assays (IC50 = 7.3 and 17.2 nM, respectively). A second group of seven disintegrins contained the RGDNP sequence and were found to be more potent inhibitors of vitronectin binding to alpha v beta 3 than fibrinogen binding to GPIIb-IIIa (IC50 = 4.3 and 19 nM, respectively). The RGDNP containing disintegrins were also greater than 10-fold more potent than RGDW containing disintegrins in blocking the adhesion of cells mediated by alpha 5 beta 1. These data illustrate that amino acid sequences immediately adjacent to the RGD site of disintegrins can create an extended RGD locus which coupled with conformational display of the RGD sequence may be involved in determining integrin selectivity and affinity. This information has been used in separate studies to design conformationally constrained integrin antagonists with high affinity for platelet GPIIb-IIIa.
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the vitronectin receptor alpha v beta 3 binds fibronectin and acts in concert with alpha 5 beta 1 in promoting cellular attachment and spreading on fibronectin
Journal of Cell Biology, 1990Co-Authors: Israel F. Charo, J. W. Smith, L Nannizzi, David A. ChereshAbstract:The vitronectin receptor (alpha v beta 3) is a member of the integrin superfamily of adhesive protein receptors that mediate a wide spectrum of adhesive cellular interactions, including attachment to vitronectin, von Willebrand factor, fibrinogen, and thrombospondin. We have studied the binding of fibronectin to the purified vitronectin receptor, and the role of this receptor in the attachment of cells to fibronectin. A solid-phase microtiter assay was developed to investigate the binding properties of the vitronectin receptor. Purified alpha v beta 3 bound fibronectin with high affinity in a saturable, divalent cation-dependent manner. Binding was inhibited by soluble vitronectin, by RGD-containing peptides, and by LM609, a monoclonal antibody against the vitronectin receptor known to inhibit the binding of adhesive proteins to alpha v beta 3. Immunoinhibition experiments showed that M21 human melanoma cells, which express the fibronectin receptor, alpha 5 beta 1, as well as alpha v beta 3, used both of these integrins to attach and spread on fibronectin. In support of this finding, M21-L cells, a variant cell line that specifically lacks alpha v beta 3 but expresses alpha v beta 1, attached and spread poorly on fibronectin. In addition, alpha v beta 3 from surface-labeled M21 cells was retained, and selectively eluted by RGDS from a fibronectin affinity column. These results indicate that alpha v beta 3 acts in concert with alpha 5 beta 1 in promoting fibronectin recognition by these cells. We conclude that fibronectin binds to the alpha v beta 3 vitronectin receptor specifically and with high affinity, and that this interaction is biologically relevant in supporting cell adhesion to matrix proteins.
