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Signaling through the PSGL‐1 cytoplasmic domain to activate β2‐integrin‐mediated slow rolling of neutrophils

Interactions of selectins with the leukocyte mucin P‐selectin glycoprotein ligand‐1 (PSGL‐1) mediate rolling on vascular surfaces. Engagement of PSGL‐1 during neutrophil rolling on P‐ or E‐selectin activates integrin LFA‐1 to slow rolling on ICAM‐1 by a pathway that requires the tyrosine kinase Syk. Based primarily on studies of cell lines, the cytoplasmic domain has been suggested to localize PSGL‐1 in uropods of polarized cells, to be required for rolling, and to mediate signaling through Syk or the lipid kinase PI3Kδ. To study the functions of the cytoplasmic domain in primary leukocytes, we generated mice expressing PSGL‐1 without the cytoplasmic domain. Surprisingly, leukocytes from these mice localized PSGL‐1 normally to microvilli, uropods, and lipid rafts, and they rolled on P‐selectin under flow. However, neutrophils expressing PSGL‐1 without the cytoplasmic domain did not exhibit LFA‐1‐mediated slow rolling on P‐selectin and ICAM‐1. PSGL‐1 signaling to slow rolling of wild‐type neutrophils required lipid rafts, Src family kinases, Syk, and the Tec kinase Btk, but not PI3K. These data demonstrate that the cytoplasmic domain of PSGL‐1 is dispensable for membrane localization and for rolling on P‐selectin, but is required to initiate a Syk‐dependent, PI3K‐independent pathway to activate LFA‐1 to slow neutrophil rolling on ICAM‐1.