Oxidant inhibition of αLβ2 integrin adhesion: evidence for coordinate effects on conformation and cytoskeleton linkage

Edwards, Bruce S.; Southon, Eileen; Curry, Mark S.; Salazar, Francisco González; Gale, James M.; Robinson, Martyn K.; Graf, Liselotte; Born, Jerry L.

doi:10.1002/jlb.63.2.190

Cited by 12 publications

(10 citation statements)

References 40 publications

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“…Thus, tying up free cysteines required in a multistep process of disulfide bond reshuffling prevents activation. These mechanistic observations are likely to explain prior observations showing that DTT activates ␣ IIb ␤ 3 on platelets (39), ␣ L ␤ 2 on monocytes (44,45), and even ␣ 5 ␤ 1 on the cell surface (46). Even though DTTinduced activation is not likely to recapitulate all of the steps involved in physiologic activation, the fact that biotin-BMCC blocks ADP-induced aggregation (Fig.…”

Section: Discussionmentioning

confidence: 60%

A Redox Site Involved in Integrin Activation

Yan¹,

Smith

2000

Journal of Biological Chemistry

135

108

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Integrin adhesion receptors contain an on/off switch that regulates ligand binding affinity and cell adhesion. The switch from "off" to "on" is commonly referred to as integrin activation. The objective of this study was to gain insight into the nature of the on/off switch in platelet integrin ␣ IIb ␤ 3 . Here, we show that a select group of the cysteines, located within the extracellular cysteinerich domain of the ␤ subunit, remain unpaired. These unpaired cysteine residues exhibit the properties of a redox site involved in integrin activation. Alterations to the redox site prevent the inter-conversion between resting and active integrin. Altogether, the study establishes integrin as a direct target for redox modulation, revealing an unappreciated link between cell adhesion and redox biology.Integrins are transmembrane receptors that mediate cell adhesion and cell migration (1, 2). The integrin protein family is directly involved in most cell-matrix contacts and cell adhesion events. Many pathologic events, including tumor progression, angiogenesis, and vascular disease, also involve integrins (3-5). In most cases cell adhesion is stringently regulated, both spatially and temporally. Spatial regulation is achieved by the expression patterns of the integrins and their various ligands. Temporal regulation of adhesion is conferred by a process called integrin "activation." Activation unshields the integrin ligand binding site, increasing its ligand binding affinity. The activation, and de-activation, of integrins is crucial to events like morphogenesis, tumor cell invasion, and platelet aggregation (6 -8).The subject of this study is platelet integrin ␣ IIb ␤ 3 , an excellent paradigm of the integrin protein family. Integrin ␣ IIb ␤ 3 is a particularly relevant model for the study of integrin activation because its function on the platelet requires physiologic activation (9). Integrin ␣ IIb ␤ 3 is maintained in a resting state on circulating platelets. However, agonists like ADP or thrombin induce activation of the integrin. This activation facilitates the binding of soluble fibrinogen, leading to the formation of a platelet aggregate, or thrombus, that halts the loss of blood. Consequently, activation of ␣ IIb ␤ 3 is key for normal hemostasis. Importantly, though, improper activation of ␣ IIb ␤ 3 can have lethal consequences. Rupture of atherosclerotic plaques can cause activation of ␣ IIb ␤ 3 on platelets and can lead to myocardial infarct (10).The precise mechanism by which integrins are activated and de-activated is still not completely understood. A significant body of work has focused on how alterations to integrin cytoplasmic domains control activation. In one well supported model, changes in the conformation of the cytoplasmic tails are thought to release a conformational constraint, or open an "integrin hinge" (11). The release of this hinge is believed to translate into conformational rearrangements in the extracellular face of the integrin that expose the ligand binding site. The physical association of...

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Section: Discussionmentioning

confidence: 60%

A Redox Site Involved in Integrin Activation

Yan¹,

Smith

2000

Journal of Biological Chemistry

135

108

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“…We also show in Tables 1 and 2 that adding DTT to Mn 21 leads to slower ligand dissociation and increased separation distance. The dithiol compounds are well-known modulators of integrin-dependent adhesion (Edwards et al, 1995(Edwards et al, , 1998Schwartz and Harlan, 1989). Thus, in three independent conditions that are highly unlikely to have similar consequences for lateral distribution of donor or acceptor, there is a correlation between ligand binding to the integrin and the distance of closest approach of R18 to the ligand binding site.…”

Section: Distance Of Closest Approachmentioning

confidence: 99%

FRET Detection of Cellular α4-Integrin Conformational Activation

Chigaev

Buranda

Dwyer

et al. 2003

Biophysical Journal

120

168

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Integrins are cell adhesion receptors, expressed on every cell type, that have been postulated to undergo conformational changes upon activation. Here, different affinity states were generated by exposing alpha4-integrins to divalent ions or by inside-out activation using a chemokine receptor. We probed the dynamic structural transformation of the integrin on live cells using fluorescence resonance energy transfer (FRET) between a peptide donor, which specifically binds to the alpha4-integrin, and octadecyl rhodamine B acceptors incorporated into the plasma membrane. We analyzed the data using a model that describes FRET between a random distribution of donors and acceptors in an infinite plane. The distance of closest approach was found to vary with the affinity of the integrin. The change in distance of closest approach was approximately 50 A between resting and Mn2+ activated receptors and approximately 25 A after chemokine activation. We used confocal microscopy to probe the lateral organization of donors and acceptors subsequent to integrin activation. Taken together, FRET and confocal results suggest that changes in FRET efficiencies are primarily due to the vertical extension of the integrin. The coordination between the extension of alpha4-integrin and its affinity provides a mechanism for Dembo's catch-bond concept.

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“…In vitro, exposure to high glucose concentrations leads to the upregulation of some adhesion molecules on some cell lines, 3 and this modulation may be antioxidant sensitive. 4 Increased expression of some key adhesion molecules (such as Mac-1) on monocyte-macrophages and neutrophils can occur within minutes through mobilization from an intracellular vesicular storage compartment 5,6 and may selectively increase in response to cytokines, proinflammatory mediators, or lipid oxidation products 6 -8 through antioxidantsensitive mechanisms. 9 -11 This expression is of particular interest in type 2 diabetes, which is associated with increased rates of macrovascular disease and vascular events and in which acute or postprandial hyperglycemia may be an independent risk for vascular disease as it is in individuals without diabetes.…”

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confidence: 99%

Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients

Sampson

Davies

Brown

et al. 2002

ATVB

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Objective-We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. Methods and Results-Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (PϽ0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (Pϭ0.03). Conclusions-Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.

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Oxidant inhibition of αLβ2 integrin adhesion: evidence for coordinate effects on conformation and cytoskeleton linkage

Cited by 12 publications

References 40 publications

A Redox Site Involved in Integrin Activation

A Redox Site Involved in Integrin Activation

FRET Detection of Cellular α4-Integrin Conformational Activation

Monocyte and Neutrophil Adhesion Molecule Expression During Acute Hyperglycemia and After Antioxidant Treatment in Type 2 Diabetes and Control Patients

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