title: Unexpected signals in a system subject to kinetic proofreading.
abstract: When multivalent ligands attach to IgEs bound to the receptors with high affinity for IgE on mast cells, the receptors aggregate, tyrosines on the receptors become phosphorylated, and a variety of cellular responses are stimulated. Prior studies, confirmed here, demonstrated that the efficiency with which later events are generated from earlier ones is inversely related to the dissociation rate of the aggregating ligand. This finding suggests that the cellular responses are constrained by a "kinetic proofreading" regimen. We have now observed an apparent exception to this rule. Doses of the rapidly or slowly dissociating ligands that generated equivalent levels of tyrosine-phosphorylated receptors comparably stimulated a putatively distal event: transcription of the gene for monocyte chemoattractant protein 1. Possible explanations of this apparent anomaly were explored.
authors.affiliation: Section on Chemical Immunology, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Haleem-Smith
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Metzger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015550:Cell Degranulation; D018932:Chemokine CCL2 / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D016762:Genes, fos; D006596:Hexosaminidases / Q000378:metabolism; D007073:Immunoglobulin E / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D015471:Leukemia, Basophilic, Acute; D008024:Ligands; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017455:Receptors, IgE; D003609:Dactinomycin; D019000:Phosphotyrosine; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat; D006596:Hexosaminidases