title: MAP-kinase dependent induction of monocytic procoagulant activity by beta2-integrins.
abstract: beta2-Integrin adhesion molecules play crucial roles in monocyte transmigration and adherence to the inflamed extracellular matrix. While integrin engagement contributes to inflammatory cell activation, little is known about the precise signaling pathways that are important to integrin-dependent monocyte activation. We examined the role of tyrosine phosphorylation and extracellular-signal regulated kinase (ERK) activity in beta2-integrin signaling in monocytes. Cross-linking of the LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) integrins on the surface of THP-1 monocytic cells induced the accumulation of tyrosine phosphoproteins. As part of this signal both ERK-1 and ERK-2 are tyrosine phosphorylated. In vitro kinase assays documented an increase in ERK-2 activity following both LFA-1 and MAC-1 cross-linking. beta2-Integrin cross-linking also led to a marked increase in 4-h procoagulant activity (PCA) in THP-1 cells and purified human monocytes. Inhibition of tyrosine phosphorylation by genistein (10 microg/ml), or selective ERK inhibition with PD98059 (10 microM), was able to block the integrin-dependent induction of PCA in both THP-1 cells and human monocytes. Thus, beta2 integrin signaling in monocytic cells can flow through the tyrosine phosphorylation and activation of the ERK mitogen activated protein kinases, which is essential for the subsequent expression of tissue factor. These results suggest that the ERK proteins likely function to integrate various adhesion-dependent signals during the process of monocyte transmigration.
authors.affiliation: Department of Surgery, Division of General Surgery, University of Toronto and Toronto Hospital, Toronto, Ontario, M5G 2C4, Canada.
authors.forename: I D
authors.initials: ID
authors.lastname: McGilvray
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: A C
authors.initials: AC
authors.lastname: Wei
authors.forename: O D
authors.initials: OD
authors.lastname: Rotstein
mesh_terms: D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D018821:CD18 Antigens / Q000378:metabolism*; D002460:Cell Line; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D016177:Macrophage-1 Antigen / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001779:Blood Coagulation Factors; D018821:CD18 Antigens; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018836:Inflammation Mediators; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; C045071:leukocyte procoagulant activity; D019000:Phosphotyrosine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one