The IIb-IIIa glycoprotein complex that mediates platelet aggregation is directly implicated in leukocyte adhesion

Burns, Gordon F.; Cosgrove, Leah; Triglia, Tony; Beall, J. A.; López, Angel F.; Werkmeister, Jerome A.; Begley, C. Glenn; Haddad, Albert P.; d’Apice, Anthony J.F.; Vadas, Mathew A.; Cawley, James F.

doi:10.1016/0092-8674(86)90391-0

Cited by 82 publications

(28 citation statements)

References 49 publications

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“…Leukocytes increase fibrinogen synthesis by secreting interleukin-6 under stimulus from fibrinogen degradation products [2]. The pathogenetic role of inflammation in the development of atherosclerosis is supported by recent studies showing that interleukin-1 and tumour necrosis factor are able to reverse the functional non-thrombogenic properties of normal endothelium towards prothrombotic changes, enhancing the generation of thrombin at the endothelial surface [3][4][5][6]. Polymorphonuclear leukocytes can activate platelets [6], which stimulate the adherence of monocytes to surfaces [5] and the endothelial expression of leukocyte adhesion molecules [7].…”

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confidence: 77%

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Fibrin(ogen) and diabetes mellitus: don't forget fibrinolysis

1997

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confidence: 77%

“…Inflammation is associated with both hypercoagulability (increased fibrinogen, factor VIII, platelets) [1][2][3][4][5][6][7] and hypofibrinolysis (increased expression of plasminogen activator inhibitor-1, PAI-1) [10]. Plasma levels of fibrinogen were found to be associated with the severity of atheromatous involvement of the arterial walls [11].…”

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confidence: 99%

Fibrin(ogen) and diabetes mellitus: don't forget fibrinolysis

1997

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“…The final products were soluble in aqueous buffers and were homogenous as assessed by SDS-PAGE. When immobilized on microtiter plates, each of the recombinant ␤ 3 fragments reacted with mAb 937 to ␤ 3 -(101-109) (53) and mAb 25E11 to ␤ 3 -(237-248) (54) in an enzymelinked immunosorbent assay format. Circular dichroism was performed on the renatured recombinant fragments.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Two Cation Binding Sites in the Integrin β3 Subunit

Cierniewska-Cieslak

Cierniewski

Błędzka

et al. 2002

Journal of Biological Chemistry

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The midsegment of the ␤ 3 subunit has been implicated in the ligand and cation binding functions of the ␤ 3 integrins. This region may contain a metal ion-dependent adhesion site (MIDAS) and fold into an I domain-like structure. Two recombinant fragments, ␤ 3 -(95-373) and ␤ 3 -(95-301), were expressed and found to bind fibrinogen. ␣ IIb ␤ 3 is a typical member of the integrin family of cell adhesion receptors (1), being composed of an ␣ (␣ IIb ) and a ␤ (␤ 3 ) subunit, which associate to form a noncovalent heterodimer. This integrin is the most abundant membrane protein on the platelet surface and serves as a receptor for multiple adhesive proteins including fibrinogen (Fg).1 Two sets of peptides (HHLGGAKQAGDV, corresponding to the sequence at the C terminus of the Fg ␥-chain (2) and RGDX, corresponding to a sequence present in many protein ligands of ␣ IIb ␤ 3 and recognized by many other integrins as well) define the recognition specificity of ␣ IIb ␤ 3 for its macromolecular ligands (reviewed in Ref.3). ␣ V ␤ 3 , which shares the same ␤ 3 subunit as ␣ IIb ␤ 3 , is broadly distributed and binds many but not all of the same ligands as ␣ IIb ␤ 3 , including Fg, von Willebrand factor, and fibronectin (reviewed in Refs. 4 and 5). This integrin also exhibits an RGD recognition specificity but shows a much weaker recognition of Fg ␥-chain peptides (6). Numerous studies have suggested that binding of macromolecular ligands to ␣ IIb ␤ 3 as well as ␣ V ␤ 3 involves multiple contacts in each subunit (7-13). Essential residues for ligand binding to ␣ IIb ␤ 3 reside in two major regions: a midsegment of ␤ 3 , ␤ 3 -(95-400), and the amino-terminal aspect of ␣ IIb , ␣ IIb -(1-334) (11), which contains seven structural repeats (14). The midsegment of the ␤ 3 subunit is highly conserved among integrin ␤ subunits and exhibits some structural and functional features of an I domain. I domains are present in nine integrin ␣ subunits and play major roles in the ligand binding functions of their integrin heterodimers (15)(16)(17)(18)(19)(20). The relationship between the conserved ␤ midsegments and ␣ I domains was proposed based upon similarities in their hydropathy profiles, secondary structural predictions, and mutational analyses (18, 20 -22). A central feature of I domains is a metal ion-dependent adhesion site, a MIDAS motif (15,18,19,23). In MIDAS motifs, three of the five cation coordination sites are provided by a DXSXS sequence and two other coordination sites are provided by oxygenated residues distant in the primary sequence. Mutations of the cation-coordinating residues in a MIDAS motif often cause loss of ligand binding functions of an integrin, and ligand binding sites map in close proximity to MIDAS motifs (18,24,25). The ␤ 3 midsegment does contain a 119 DXSXS sequence, and these residues also have been implicated in the ligand binding functions of ␣ IIb ␤ 3 (24, 26 -28). While there is broad consensus that the midsegment of integrin ␤ subunit contains a functional MIDAS, other structural algorithms have predicted ...

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“…Several PMN receptors have been implicated in formation of PMN-platelet conjugates, 14,15,[19][20][21][22] and their involvement in MPplatelet complexes were tested with the following blocking reagents: WAPS12.2 to P-selectin, 39 which blocks platelet association with leukocytes; PL1 to PSGL-1, 38 25E11 to the integrin ␤3 subunit, 46 VM16d to GPIb␣, which blocks its interaction with VWF and ␣ M ␤ 2 20 ; mAbs to the ␣ M or ␤ 2 subunit 40 ; and neutrophil inhibitory factor (NIF), a high-affinity ligand of ␣ M ␤ 2 , known to compete with most ␣ M ␤ 2 ligands and to block the ␣ M ␤ 2 -dependent PMN functions. 47 None of the reagents tested reduced interaction of resting MPs with platelets in a statistically significant manner (data not shown).…”

Section: Pmn-derived Mps Contain ␣ M ␤ 2 In An Active Conformationmentioning

confidence: 99%

Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

Pluskota

Woody

Szpak

et al. 2008

Blood

175

148

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IntroductionLeukocyte-platelet cross-talk plays multiple and important roles in inflammatory and thrombotic responses. 1 Activated platelets and platelet-released mediators, such as PDGF and PAF, activate leukocytes enhancing their responses such as adhesion, chemotaxis, phagocytosis, and superoxide generation. [2][3][4][5] Conversely, activated leukocytes induce platelet activation as evidenced by increased platelet P-selectin expression. 6 In vivo studies show that leukocytes and platelets colocalize within atherosclerotic and restenotic lesions, at sites of hemorrhage and ischemia-reperfusion injury. [7][8][9][10] Indeed, increased levels of leukocyte-platelet aggregates are found in patients with diabetes, acute coronary syndromes, trauma, and sepsis. [11][12][13] Numerous studies have analyzed the receptors involved in leukocyte-platelet interactions. P-selectin on activated platelets binds PSGL-1 on leukocytes 14,15 to support their rolling on adherent platelets and to activate leukocyte integrin ␣ M ␤ 2 , which mediates firm leukocyte adhesion. [16][17][18] Several ␣ M ␤ 2 counterreceptors on platelets have been proposed, including Fg-bound ␣ IIb ␤ 3 , 19 GPIb␣,20,21 and JAM-3. 22 Recognition of these counterreceptors requires that ␣ M ␤ 2 be in an activated conformation. ␣ M ␤ 2 can be activated by stimulation of leukocytes by agonists and can be monitored with monoclonal antibodies (mAbs), CBRM1/5 and mAb24, which react selectively with the activated conformation.Microparticles (MPs) are released by membrane blebbing from cells undergoing activation or apoptosis. MPs are usually defined by 2 criteria: size (Ͻ 1 m) and surface expression of negatively charged phosphatidylserine (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ). MPs are not simply the markers of cell activation or damage but may exert pleiotropic effects on blood and vascular cells. MPs of platelet and endothelial origin have procoagulant and proinflammatory activities (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ) and are markers of acute coronary syndromes. 27,28 The functions of leukocyte-derived MPs are less clear. MPs shed by PMNs behave as inflammatory mediators and activate endothelial cells 29,30 but also exert antiinflammatory effects on macrophages. 31 One of the most important features of leukocyte-derived MPs is the expression of tissue factor 32 and negatively charged phospholipids, suggesting that they may contribute to blood coagulation. Indeed, in vivo studies have shown that leukocyte MPs are captured by activated platelets within thrombi by a P-selectin/PSGL-1-dependent mechanism that leads to accumulation of tissue factor and ultimately enhanced fibrin deposition. 33,34 Although the interactions of leukocyte-derived MPs with activated platelets have been well documented, additional mechanisms in which leukocyte MPs may activate resting platelets, when platelet P-selectin expression is low, have not been examined. In this study, we show...

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The IIb-IIIa glycoprotein complex that mediates platelet aggregation is directly implicated in leukocyte adhesion

Cited by 82 publications

References 49 publications

Fibrin(ogen) and diabetes mellitus: don't forget fibrinolysis

Fibrin(ogen) and diabetes mellitus: don't forget fibrinolysis

Identification and Characterization of Two Cation Binding Sites in the Integrin β3 Subunit

Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

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