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T Kunicki

Publications and source records attributed to T Kunicki.

9 recordsLinked to original sources
PubMed2001

Platelet receptor polymorphisms and thrombotic risk.

Plaque rupture and/or endothelial damage lead to exposure of von Willebrand factor and collagen which facilitate the adhesion of circulating platelets via glycoprotein Ib-IX-V and the integrin alpha2 beta1, respectively, to the damaged vessel wall. This process activates the platelet and leads to a conformational change of a second integrin alphaIIb beta3 that facilitates fibrinogen binding and platelet aggregation. Thrombin generated at the blood-plaque interface converts fibrinogen to fibrin, which stabilizes thrombus growth. Therefore, any genetic differences that might alter surface expression or activity of these receptors could influence risk for adverse outcomes as a result of the haemostatic process. In the last 5 years, there has been a rapid accumulation of the literature concerning the relationship between genetic variations in platelet glycoproteins and risk for coronary heart disease. In this chapter, we present a comprehensive review of the impact of platelet receptor polymorphisms and thrombotic risk.

Antigens, CD↗
PubMed1996

Activation of the integrin alpha v beta 3 involves a discrete cation-binding site that regulates conformation.

"Activation" of integrins is involved in the dramatic transition of leukocytes and platelets from suspension to adhesion. The integrin alpha v beta 3 is not known to take part in this sort of transition, even though it shares its beta subunit with alpha IIb beta 3, the activable integrin on platelets. In the context of a constitutively adhered cell, changes in activation state may be more subtle in their effects, but nonetheless important in regulating cell behavior. We hypothesized that alpha v beta 3 can undergo conformational changes analogous to those associated with alpha IIb beta 3 activation. Accordingly, we examined alpha v beta 3 on the surface of M21 cells (a human melanoma cell line) and found that, like alpha IIb beta 3, it can undergo conformational changes upon binding of a ligand analog and can be activated for ligand binding and migration by a monoclonal antibody directed against beta 3. Modulation of the binding of this activating antibody, AP5, ligand binding, and antibody-mediated activation all are associated with a discrete cation-binding site shared in both alpha IIb beta 3 and alpha v beta 3. Based on a measured Ki, this site has an apparent Kd for calcium of approximately 20 microM. At physiological levels of calcium, about 40% of the total alpha v beta 3 on a cell's surface is in a conformation detected by AP5. The data suggest a model for both alpha v beta 3 and alpha IIb beta 3 function in which the molecule can exist in either of (at least) two conformational states, one stabilized either by AP5 or ligand binding, refractory to calcium binding, and enhanced for ligand recognition, the other stabilized by calcium binding and refractory to AP5 and ligand binding. Functional analysis suggests that AP5 activates alpha v beta 3 by preventing occupation of this calcium site, and that the activated form of alpha v beta 3 differs functionally from the basal form. The active form is more conducive to migration and the basal to tight adhesion.

Binding Sites↗
PubMed1995

The activation state of the integrin alpha IIb beta 3 affects outside-in signals leading to cell spreading and focal adhesion kinase phosphorylation.

Integrins bind extracellular matrix and transduce signals mediating cell adhesion, spreading, and migration. It is unclear how these distinct responses follow from a common event: integrin clustering. We examined the relationship between integrin-mediated signals and the integrin's activation state using a cell line expressing alpha IIb beta 3 (Clone B) and a panel of monoclonal antibodies against this integrin. Non-activating antibodies used to cluster alpha IIb beta 3 stimulated focal adhesion kinase (FAK) phosphorylation, regardless of affinity, subunit specificity, or ligand-blocking phenotype. Coated on plastic, these antibodies supported cell adhesion, spreading, and FAK phosphorylation. In contrast, clustering of alpha IIb beta 3 induced with activating antibodies, or binding of soluble fibrinogen to antibody-activated alpha IIb beta 3, did not induce FAK phosphorylation. Thus, clustering of alpha IIb beta 3 on Clone B does not necessarily result in FAK phosphorylation. Coated on plastic, activating antibodies supported cell adhesion, but not spreading or FAK phosphorylation. Therefore, it appears the resting, not the active form of alpha IIb beta 3, induces cell spreading and FAK phosphorylation in Clone B. These data indicate that "inside-out" signals may alter not only the binding specificity of an integrin, but the "outside-in" biochemical signals that integrin initiates as well. This activation state-linked signaling represents a novel mechanism, which may explain how diverse cellular responses are induced by integrin-matrix interactions.

Antibodies, Monoclonal↗
PubMed1979

[Immunochemical study of protein anomalies in platelets of patients with Glanzmann's thrombasthenia and Bernard-Soulier syndrome].

Crossed immunoelectrophoresis of "Triton X-100" solubilized proteins from (125I) iodinated normal and abnormal (Bernard-Soulier and thrombasthenic) platelets was performed using rabbit antibodies raised against whole, normal platelets. In Bernard-Soulier platelets neither of the two surface oriented forms of GP I, glycocalicin and glycoprotein Ib (band 13) were detected. In two patients with type I thrombasthenia, the most prominent precipitate (No. 16) and platelet fibrinogen (No 24) were not detected whereas in one patient with type II thromblasthenia, fibrinogen was normally detected and the amount of protein 16 was around 15% of the normal level. The alloantibody IgG L..., able to induce a "thrombasthenic-like" reactivity in normal human platelets, has been shown to be directed against protein 16.

Animals↗