John Libbey Eurotext

Hématologie

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Platelet signal transduction pathways : could we organize them into a « hierarchy » ? Volume 4, issue 5, Septembre-Octobre 1998

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Platelet activation results in shape change, release of granule contents, aggregation and clot retraction. An intense intracellular « machinery » is engaged to achieve these functions. Thrombin is one of the most important agonists for platelet recruitment and aggregation which is mediated by the binding of fibrinogen to its adhesive receptor : the GPIIb/IIIa complex or integrin alphaIIb beta3. The numerous biological processes consecutive to thrombin binding to platelet membrane are mainly controlled by phosphorylation mechanisms organized into signalling pathways. Schematically, the PLC beta pathway activated by G protein coupled to the seven transmembrane thrombin receptor, provides the first intracellular relay and would generate regulators such as PKC, phosphorylated pleckstrin but also modifications of the intracellular domain of beta3. This « inside-out » signalling would lead to some changes into the extracellular domain of GPIIb/IIIa increasing access of fibrinogen to the receptor. Ligand interaction with GPIIb/IIIa induced reorganization of cytoskeleton and would mediate the « outside-in » signals which involve a series of intracellular events including tyrosine kinases, phosphatidylinositol 3 kinases, MAP kinases, phosphatases... Some of these pathways and /or signalling metabolites could be associated to some well characterized platelet functions : cortactin phosphorylation is involved in platelet shape change, phosphatidylinositol 3 kinase (p 85) in the stabilisation of platelet aggregates and MAP kinase (p 44) in post-aggregation events. But in fact the sequence of events which has been described, has to be viewed as integrated networks. Three biochemical processes at least govern the highly integrated organization to send just the appropriate quanta of signal for the specific need : the reorganization of the cytoskeleton following the binding of fibrinogen to alpha IIb beta3, the structure of the signal transducers that contain SH2, SH3, and PH domains leading to the formation of macromolecules of signalling and the cross-talk phenomenons between the different pathways.