Abstract
Phosphatidylinositol 3-kinase (PI3K) isoforms PI3Kbeta and PI3Kgamma are implicated in platelet adhesion, activation, and aggregation, but their relative contribution is still unclear or controversial. Here, we report the first comparative functional analysis of platelets from mice expressing a catalytically inactive form of PI3Kbeta or PI3Kgamma. We demonstrate that both isoforms were similarly required for maximal activation of the small GTPase Rap1b and for complete platelet aggregation upon stimulation of G protein-coupled receptors for adenosine 5'-diphosphate (ADP) or U46619. Their contribution to these events, however, was largely redundant and dispensable. However, PI3Kbeta, but not PI3Kgamma, enzymatic activity was absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream of the immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor glycoprotein VI (GPVI). Moreover, PI3Kbeta was a major essential regulator of platelet adhesion to fibrinogen and of integrin alpha(IIb)beta(3)-mediated spreading. These results provide genetic evidence for a crucial and selective role of PI3Kbeta in signaling through GPVI and integrin alpha(IIb)beta(3).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Amino Acid Motifs / genetics
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Animals
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Blood Platelets / enzymology*
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Fibrinogen / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Platelet Adhesiveness / drug effects
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Platelet Adhesiveness / physiology
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Platelet Aggregation / drug effects
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Platelet Aggregation / physiology*
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Platelet Glycoprotein GPIIb-IIIa Complex / genetics
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Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
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Platelet Membrane Glycoproteins / genetics
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Platelet Membrane Glycoproteins / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Purinergic P2 Receptor Agonists
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Receptors, Purinergic P2 / genetics
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Receptors, Purinergic P2 / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Vasoconstrictor Agents / pharmacology
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rap GTP-Binding Proteins / genetics
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rap GTP-Binding Proteins / metabolism
Substances
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Isoenzymes
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Platelet Glycoprotein GPIIb-IIIa Complex
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Platelet Membrane Glycoproteins
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Purinergic P2 Receptor Agonists
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Receptors, Purinergic P2
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Vasoconstrictor Agents
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platelet membrane glycoprotein VI
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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Fibrinogen
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Rap1b protein, mouse
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rap GTP-Binding Proteins