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Kinetic Proofreading of Ligand-FcRI Interactions May Persist beyond LAT Phosphorylation¹

Chikako Torigoe^*,, James R. Faeder, Janet M. Oliver and Byron Goldstein^2,

^* Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; Department of Pathology and Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, NM 87131; and Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545

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 FcRI, 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 Ca²⁺, and degranulation exhibit kinetic proofreading downstream of LAT phosphorylation. These results suggest that ligand-bound FcRI and LAT form a complex that is required for effective signal transmission.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R37 GM35556, RO1 GM49814, and P20 GM065794 and by the Department of Energy through contract W-7405-ENG-36.

² Address correspondence and reprint requests to Dr. Byron Goldstein, Los Alamos National Laboratory, Theoretical Biology and Biophysics, Los Alamos, NM 87545. E-mail address: bxg{at}lanl.gov

³ Abbreviations used in this paper: LAT, linker for activation of T cells; 2-NP, 2-nitrophenyl; PLC, phospholipase C; RBL, rat basophilic leukemia.