title: Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes.
abstract: Engagement of adhesion molecules on monocytes and other myeloid leukocytes, which are effector cells of the innate immune system, not only tethers the leukocytes in place but also transmits outside-in signals that induce functional changes and alter gene expression. We found that a subset of mRNAs that are induced or amplified by adhesion of human monocytes to P-selectin via its surface ligand, P-selectin glycoprotein 1, have characteristics that suggest specialized translational control. One of these codes for urokinase plasminogen activator receptor (UPAR), a critical surface protease receptor and regulator of cell adhesion and migration. Although UPAR transcripts are induced by adhesion, rapid synthesis of the protein uses constitutive mRNA without a requirement for new transcription and is regulated by mammalian target of rapamycin, demonstrating new biologic roles for the signal-dependent translation pathway controlled by this intracellular kinase. The synthesis of UPAR in monocytic cells is also regulated by eukaryotic translation initiation factor 4E, a second key translational checkpoint, and phosphorylation of eukaryotic translation initiation factor 4E is induced by adhesion of monocytes to P-selectin. Translationally controlled display of UPAR by monocytes confers recognition of the matrix protein, vitronectin. Adhesion-dependent signaling from the plasma membrane to translational checkpoints represents a previously unrecognized mechanism for regulating surface phenotype that may be particularly important for myeloid leukocytes and other cells that are specialized for rapid inflammatory and vascular responses.
authors.affiliation: The Eccles Program in Human Molecular Biology and Genetics, and Department of Internal Medicine and Experimental Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Mahoney
authors.forename: A S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: D A
authors.initials: DA
authors.lastname: Dixon
authors.forename: T
authors.initials: T
authors.lastname: McIntyre
authors.forename: S M
authors.initials: SM
authors.lastname: Prescott
authors.forename: G A
authors.initials: GA
authors.lastname: Zimmerman
mesh_terms: D002448:Cell Adhesion / Q000235:genetics*; D002462:Cell Membrane / Q000502:physiology; D039561:Eukaryotic Initiation Factor-4E; D005786:Gene Expression Regulation; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D019007:P-Selectin / Q000502:physiology; D010448:Peptide Initiation Factors / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D019007:P-Selectin; C524898:PLAUR protein, human; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases