Abstract
In inflamed venules, neutrophils rolling on E-selectin induce integrin alpha(L)beta(2)-dependent slow rolling on intercellular adhesion molecule-1 by activating Src family kinases (SFKs), DAP12 and Fc receptor-gamma (FcRgamma), spleen tyrosine kinase (Syk), and p38. E-selectin signaling cooperates with chemokine signaling to recruit neutrophils into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) as the essential E-selectin ligand and Fgr as the only SFK that initiate signaling to slow rolling. In contrast, we found that E-selectin engagement of PSGL-1 or CD44 triggered slow rolling through a common, lipid raft-dependent pathway that used the SFKs Hck and Lyn as well as Fgr. We identified the Tec kinase Bruton tyrosine kinase as a key signaling intermediate between Syk and p38. E-selectin engagement of PSGL-1 was dependent on its cytoplasmic domain to activate SFKs and slow rolling. Although recruiting phosphoinositide-3-kinase to the PSGL-1 cytoplasmic domain was reported to activate integrins, E-selectin-mediated slow rolling did not require phosphoinositide-3-kinase. Studies in mice confirmed the physiologic significance of these events for neutrophil slow rolling and recruitment during inflammation. Thus, E-selectin triggers common signals through distinct neutrophil glycoproteins to induce alpha(L)beta(2)-dependent slow rolling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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E-Selectin / physiology*
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / physiology*
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In Vitro Techniques
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Leukocyte Rolling / physiology*
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Lymphocyte Function-Associated Antigen-1 / physiology*
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Microdomains / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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Neutrophils / physiology
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P-Selectin / physiology
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Phosphatidylinositol 3-Kinases / physiology
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-hck / physiology
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / physiology
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src-Family Kinases / physiology
Substances
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Cd44 protein, mouse
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E-Selectin
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Hyaluronan Receptors
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Lymphocyte Function-Associated Antigen-1
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Membrane Glycoproteins
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P-Selectin
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P-selectin ligand protein
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Proto-Oncogene Proteins
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse
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Hck protein, mouse
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Proto-Oncogene Proteins c-hck
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lyn protein-tyrosine kinase
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proto-oncogene proteins c-fgr
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src-Family Kinases
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p38 Mitogen-Activated Protein Kinases