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Mueller, H, Stadtmann, A, Van Aken, H, Hirsch, E, Wang, D, Ley, K and Zarbock, A (2010) Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways. Blood 115:3118-27


Selectins mediate leukocyte rolling, trigger beta(2)-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) gamma2- and phosphoinositide 3-kinase (PI3K) gamma-dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP(3)), and inducing E-selectin-mediated slow rolling. Inhibition of this signal-transduction pathway diminished Galpha(i)-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Galpha(i)-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk(-/-) and Plcg2(-/-) mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.


PubMed PMC2858472 Online version:10.1182/blood-2009-11-254185


Animals; Antigens, CD18/metabolism; Cell Adhesion/drug effects; Chemokines/pharmacology; E-Selectin/metabolism; Enzyme Activation/drug effects; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism; Leukocyte Rolling/drug effects; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils/cytology; Neutrophils/drug effects; Neutrophils/enzymology; Phosphatidylinositol 3-Kinases/metabolism; Phospholipase C gamma/deficiency; Phospholipase C gamma/metabolism; Phosphorylation/drug effects; Protein-Tyrosine Kinases/deficiency; Protein-Tyrosine Kinases/metabolism; Signal Transduction/drug effects; p38 Mitogen-Activated Protein Kinases/metabolism



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0033625: positive regulation of integrin activation



Figure 1 - The Tec family kinase Btk is required for E-selectin–mediated slow rolling (integrin activation)

CACAO 7519

See also


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