Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes.
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.
Mahoney
T S
TS
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.
Weyrich
A S
AS
Dixon
D A
DA
McIntyre
T
T
Prescott
S M
SM
Zimmerman
G A
GA
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
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