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P-selectin primes leukocyte integrin activation during inflammation.

Nature immunology | Aug 20, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17632516

Selectins mediate leukocyte rolling and prime leukocytes for integrin-mediated leukocyte adhesion. However, neither the in vivo importance of nor the signaling pathway by which selectin-mediated integrin activation occurs has been determined. We report here that P-selectin-deficient mice manifested impaired leukocyte adhesion, which was 'rescued' by soluble P-selectin. Mechanistically, the cytoplasmic domain of P-selectin glycoprotein ligand 1 formed a constitutive complex with Nef-associated factor 1. After binding of P-selectin, Src kinases phosphorylated Nef-associated factor 1, which recruited the phosphoinositide-3-OH kinase p85-p110delta heterodimer and resulted in activation of leukocyte integrins. Inhibition of this signal-transduction pathway diminished the adhesion of leukocytes to capillary venules and suppressed peritoneal infiltration of leukocytes. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by P-selectin glycoprotein ligand 1.

Pubmed ID: 17632516 RIS Download

Mesh terms: Animals | Cell Adhesion | Chemotaxis, Leukocyte | DNA-Binding Proteins | Humans | Immunoblotting | Immunoprecipitation | Inflammation | Integrins | Leukocytes | Membrane Glycoproteins | Mice | P-Selectin | Phosphatidylinositol 3-Kinases | Signal Transduction | Transfection

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P50HL081011
  • Agency: NIAID NIH HHS, Id: R01AI064743

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