title: The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes.
abstract: Integrin-mediated cell adhesion, or cross-linking of integrins using antibodies, often results in the enhanced tyrosine phosphorylation of certain intracellular proteins, suggesting that integrins may play a role in signal transduction processes. In fibroblasts, platelets, and carcinoma cells, a novel tyrosine kinase termed pp125FAK has been implicated in integrin-mediated tyrosine phosphorylation. In some cell types, integrin ligation or cell adhesion has also been shown to result in the increased expression of certain genes. Although it seems reasonable to hypothesize that integrin-mediated tyrosine phosphorylation and integrin-mediated gene induction are related, until now, there has been no direct evidence supporting this hypothesis. In the current report, we explore the relationship between integrin-mediated tyrosine phosphorylation and gene induction in human monocytes. We demonstrate that monocyte adherence to tissue culture dishes or to extracellular matrix proteins is followed by a rapid and profound increase in tyrosine phosphorylation, with the predominant phosphorylated component being a protein of 76 kD (pp76). Tyrosine phosphorylation of pp76 and other monocyte proteins can also be triggered by incubation of monocytes with antibodies to the integrin beta 1 subunit, or by F(ab')2 fragments of such antibodies, but not by F(ab) fragments. The ligation of beta 1 integrins with antibodies or F(ab')2 fragments also induces the expression of immediate-early (IE) genes such as IL-1 beta. When adhering monocytes are treated with the tyrosine kinase inhibitors genistein or herbimycin, both phosphorylation of pp76 and induction of IL-1 beta message are blocked in a dose-dependent fashion. Similarly, treatment with genistein or herbimycin can block tyrosine phosphorylation of pp76 and IL-1 beta message induction mediated by ligation of beta 1 integrin with antibodies. These observations suggest that protein tyrosine phosphorylation is an important aspect of integrin-mediated IE gene induction in monocytes. The cytoplasmic tyrosine kinase pp125FAK, although important in integrin signaling in other cell types, seems not to play a role in monocytes because this protein could not be detected in these cells.
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599.
authors.forename: T H
authors.initials: TH
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Yurochko
authors.forename: L
authors.initials: L
authors.lastname: Kornberg
authors.forename: J
authors.initials: J
authors.lastname: Morris
authors.forename: J J
authors.initials: JJ
authors.lastname: Walker
authors.forename: S
authors.initials: S
authors.lastname: Haskill
authors.forename: R L
authors.initials: RL
authors.lastname: Juliano
mesh_terms: D016227:Benzoquinones; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation / Q000502:physiology*; D017781:Genes, Immediate-Early; D019833:Genistein; D006801:Humans; D016023:Integrins / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D015815:Cell Adhesion Molecules; D016023:Integrins; D007375:Interleukin-1; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D010750:Phosphoproteins; D011809:Quinones; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human