Abstract
The peptide LSARLAF causes alphaIIbeta3-dependent platelet activation exemplified by secretion, aggregation, spreading and adhesion on fibrinogen, and tyrosine phosphorylation. alphaIIIbeta3-dependent outside-in signal transduction induced by LSARLAF was investigated in variant thrombasthenic platelets which lack most of the cytoplasmic domain of the integrin beta3 subunit (alphaIIbbeta3 delta724). These studies revealed that only certain aspects of this alphaIIbbeta3-dependent outside-in signaling were affected by the beta3 truncation. Specifically, alphaIIbbeta3 delta724 supported LSARLAF-induced platelet aggregation, agglutination and secretion, but failed to trigger cytoskeletal reorganization and platelet spreading on fibrinogen, despite the fact that PMA-induced non alphaIIbbeta3 mediated signaling caused spreading of these platelets on fibrinogen. Thus, distinct domains of alphaIIbbeta3 are required to support different aspects of LSARLAF-induced platelet activation. Furthermore, these studies suggest that not all alphaIIbbeta3-dependent platelet responses require an intact beta3 cytoplasmic tail.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Diphosphate / pharmacology
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Adolescent
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Alleles
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Antigens, CD / chemistry
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Antigens, CD / genetics*
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Antigens, CD / physiology
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Codon, Nonsense*
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Epinephrine / pharmacology
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Frameshift Mutation*
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Hemorrhagic Disorders / blood
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Hemorrhagic Disorders / genetics
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Humans
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Integrin beta3
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Macromolecular Substances
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Male
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Oligopeptides / pharmacology*
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Phosphorylation / drug effects
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Platelet Activation / drug effects*
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Platelet Activation / physiology
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Platelet Aggregation / drug effects
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Platelet Glycoprotein GPIIb-IIIa Complex / chemistry
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Platelet Glycoprotein GPIIb-IIIa Complex / physiology*
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Platelet Membrane Glycoproteins / chemistry
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Platelet Membrane Glycoproteins / genetics*
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Platelet Membrane Glycoproteins / physiology
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Protein Processing, Post-Translational / drug effects
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / physiology
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Sequence Deletion
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Structure-Activity Relationship
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Tetradecanoylphorbol Acetate / pharmacology
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Thrombasthenia / blood
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Thrombasthenia / genetics*
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Thrombin / pharmacology
Substances
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Antigens, CD
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Codon, Nonsense
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Integrin beta3
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Macromolecular Substances
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Oligopeptides
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Platelet Glycoprotein GPIIb-IIIa Complex
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Platelet Membrane Glycoproteins
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leucyl-seryl-alanyl-arginyl-leucyl-alanyl-phenylalanine
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Adenosine Diphosphate
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Protein-Tyrosine Kinases
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Thrombin
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Tetradecanoylphorbol Acetate
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Epinephrine