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Platelet alpha IIb-beta 3 integrin engagement induces the tyrosine phosphorylation of Cbl and its association with phosphoinositide 3-kinase and Syk.

Agonist-induced platelet activation triggers 'inside-out' signalling which activates alpha IIb-beta 3, the most abundant integrin in platelet membranes. The engagement of activated alpha IIb-beta 3 integrin by linking fibrinogen is necessary for platelet aggregation, and this induces subsequent outside-in signalling, which enhances platelet activation. Here we studied the involvement of Cbl during alpha IIb-beta 3-integrin-mediated signal transduction. During thrombin-induced platelet activation, Cbl was tyrosine phosphorylated, and phosphoinositide 3-kinase (PI 3-kinase) activity measured in Cbl immunoprecipitates was increased. Both Cbl phosphorylation and its association with PI 3-kinase were dependent on alpha IIb-beta 3 engagement by linking fibrinogen. The P256 and anti-LIBS6 (ligand-induced binding site 6) antibodies, which activate platelets directly through alpha IIb-beta 3, induced Cbl phosphorylation and increased the PI 3-kinase activity associated with Cbl. Both thrombin and antibodies to alpha IIb-beta 3 induced association of Cbl with the tyrosine kinase, Syk. Experiments performed with inhibitors of tyrosine kinases indicated that both Src-family kinases and Syk contribute to phosphorylation of Cbl and its consequent association with PI 3-kinase. The results show that, following integrin alpha IIb-beta 3 engagement, Cbl is tyrosine phosphorylated, recruits PI 3-kinase to this integrin signalling pathway and possibly enhances PI 3-kinase activity, downstream of Src-family tyrosine kinases and Syk activation.

Pubmed ID: 11042121

Authors

  • Saci A
  • Rendu F
  • Bachelot-Loza C

Journal

The Biochemical journal

Publication Data

November 1, 2000

Associated Grants

None

Mesh Terms

  • Actins
  • Blood Platelets
  • Enzyme Precursors
  • Fibrinogen
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Protein v-cbl
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Platelet Activation
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Protein Binding
  • Protein-Tyrosine Kinases
  • Retroviridae Proteins, Oncogenic
  • Tyrosine
  • src-Family Kinases