Role of integrin-linked kinase in leukocyte recruitment.
Chemokines modulate leukocyte integrin avidity to coordinate adhesion and subsequent transendothelial migration, although the sequential signaling pathways involved remain poorly characterized. Here we show that integrin-linked kinase (ILK), a 59-kDa serine-threonine protein kinase that interacts principally with beta(1) integrins, is highly expressed in human mononuclear cells and is activated by exposure of leukocytes to the chemokine monocyte chemoattractant protein-1. Biochemical inhibitor studies show that chemokine-triggered activation of ILK is downstream of phosphoinositide 3-kinase. In functional assays under physiologically relevant flow conditions, overexpression of wild-type ILK in human monocytic cells diminishes beta(1) integrin/vascular cell adhesion molecule-1-dependent firm adhesion to human endothelial cells. These data implicate ILK in the dynamic signaling events involved in the regulation of leukocyte integrin avidity for endothelial substrates.
Friedrich
Erik B
EB
Center for Immunology and Inflammatory Diseases, Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Sinha
Sumita
S
Li
Ling
L
Dedhar
Shoukat
S
Force
Thomas
T
Rosenzweig
Anthony
A
Gerszten
Robert E
RE
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000099200:Scaffold Protein ILK
D018932:Chemokine CCL2; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019010:Vascular Cell Adhesion Molecule-1; D000099200:Scaffold Protein ILK