Importance of Selectin-mediated Leukocyte Priming in Inflammation: P- selectin Reversibly Phosphorylates Nafl/PSGL-1 Cytoplasmic Domain Complex and Dynamically Recruits Phosphatidylinositol-3 Kinase for Cyclic Activation and Deactivation of Leukocyte Integrin αMβ2
Geng, Zhen H.
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P-selectin (CD62P) interacts with P-selectin glycoprotein ligand-1 (PSGL-1, CD162) for leukocyte rolling, whereas p2-integrins interact with immunoglobulin superfamily of cell adhesion molecules for leukocyte adhesion. This study reports that P-selectin oscillates the cell-surface clustering, the conformation, and the ligand-binding activity of αMβ2- Furthermore, P-selectin-/- and PSGL-/- null mice manifested dramatic reductions of leukocyte adhesion, which could be 'rescued' by engagement of PSGL-1 with P-selectin or PSGL-1antibody in P-selectin-/- null mice.Mechanistically, the cytoplasmic domain of PSGL-1 was found to form a stable complex with Nafl (Nef-associated factor 1). Cross- linking of PSGL-1by P-selectin reversibly phosphorylated Nafl, which dynamically triggered recruitment of p85/pll08 heterodimer of phosphatidylinositol-3 kinase and activation of otMp2. Our results thus demonstrate the functional importance of P-selectin- mediated leukocyte priming and delineate a novel PSGL-1 signal transduction pathway leading to intracellular activation of leukocyte integrins.
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