Kinetic proofreading of ligand-FcepsilonRI interactions may persist beyond LAT phosphorylation.
Cells may discriminate among ligands with different dwell times for receptor binding through a mechanism called kinetic proofreading in which the formation of an activated receptor complex requires a progression of events that is aborted if the ligand dissociates before completion. This mechanism explains how, at equivalent levels of receptor occupancy, a rapidly dissociating ligand can be less effective than a more slowly dissociating analog at generating distal cellular responses. Simple mathematical models predict that kinetic proofreading is limited to the initial complex; once the signal passes to second messengers, the dwell time no longer regulates the signal. This suggests that an assay for kinetic proofreading might be used to determine which activation events occur within the initial signaling complex. In signaling through the high affinity IgE receptor FcepsilonRI, the transmembrane adaptor called linker for activation of T cells (LAT) is thought to nucleate a distinct secondary complex. Experiments in which the concentrations of two ligands with different dwell times are adjusted to equalize the level of LAT phosphorylation in rat basophilic leukemia 2H3 cells show that Erk2 phosphorylation, intracellular Ca(2+), and degranulation exhibit kinetic proofreading downstream of LAT phosphorylation. These results suggest that ligand-bound FcepsilonRI and LAT form a complex that is required for effective signal transmission.
Torigoe
Chikako
C
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Faeder
James R
JR
Oliver
Janet M
JM
Goldstein
Byron
B
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D045744:Cell Line, Tumor; D007700:Kinetics; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C491733:Lat protein, rat; D008024:Ligands; D008565:Membrane Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; D019950:Mitogen-Activated Protein Kinase 1