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Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways. Blood 2010 Apr 15;115(15):3118-27

Date

02/20/2010

Pubmed ID

20167705

Pubmed Central ID

PMC2858472

DOI

10.1182/blood-2009-11-254185

Scopus ID

2-s2.0-77951027428   104 Citations

Abstract

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.

Author List

Mueller H, Stadtmann A, Van Aken H, Hirsch E, Wang D, Ley K, Zarbock A

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
CD18 Antigens
Cell Adhesion
Chemokines
E-Selectin
Enzyme Activation
GTP-Binding Protein alpha Subunits, Gi-Go
Leukocyte Rolling
Mice
Mice, Inbred C57BL
Neutrophil Infiltration
Neutrophils
Phosphatidylinositol 3-Kinases
Phospholipase C gamma
Phosphorylation
Protein-Tyrosine Kinases
Signal Transduction
p38 Mitogen-Activated Protein Kinases
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5