A Mechanistic Model of Early FcεRI Signaling: Lipid Rafts and the Question of Protection from Dephosphorylation
We present a model of the early events in mast cell signaling mediated by FcεRI where the plasma membrane is composed of many small ordered lipid domains (rafts), surrounded by a non-order region of lipids consisting of the remaining plasma membrane. The model treats the rafts as transient structures that constantly form and breakup, but that maintain a fixed average number per cell. The rafts have a high propensity for harboring Lyn kinase, aggregated, but not unaggregated receptors, and the linker for the activation of T cells (LAT). Phosphatase activity in the rafts is substantially reduced compared to the nonraft region. We use the model to analyze published experiments on the rat basophilic leukemia (RBL)-2H3 cell line that seem to contradict the notion that rafts offer protection. In these experiments IgE was cross-linked with a multivalent antigen and then excess monovalent hapten was added to break-up cross-links. The dephosphorylation of the unaggregated receptor (nonraft associated) and of LAT (raft associated) were then monitored in time and found to decay at similar rates, leading to the conclusion that rafts offer no protection from dephosphorylation. In the model, because the rafts are transient, a protein that is protected while in a raft will be subject to dephosphorylation when the raft breaks up and the protein finds itself in the nonraft region of the membrane. We show that the model is consistent with the receptor and LAT dephosphorylation experiments while still allowing rafts to enhance signaling by providing substantial protection from phosphatases.
D. Barua and B. Goldstein, "A Mechanistic Model of Early FcεRI Signaling: Lipid Rafts and the Question of Protection from Dephosphorylation," PLoS ONE, vol. 7, no. 12, PLoS ONE, Dec 2012.
The definitive version is available at https://doi.org/10.1371/journal.pone.0051669
Chemical and Biochemical Engineering
Keywords and Phrases
Immunoglobulin E; Immunoglobulin E Receptor; LAT Protein; Phosphatase; Protein Kinase Lyn, Animal Cell; Antigen Antibody Complex; Article; Enzyme Activity; Hapten Carrier Complex; Lipid Raft; Mast Cell; Membrane Component; Membrane Model; Membrane Structure; Nonhuman; Protein Aggregation; Protein Cross Linking; Protein Dephosphorylation; Rat; Signal Transduction; T Lymphocyte Activation, Animals; Calcium; Cell Membrane; Computer Simulation; Haptens; Immunoglobulin E; Intracellular Signaling Peptides And Proteins; Leukemia, Basophilic, Acute; Lipoylation; Mast Cells; Membrane Microdomains; Models, Biological; Mutation; Phosphorylation; Protein-Tyrosine Kinases; Rats; Receptors, IgE; Signal Transduction; Src-Family Kinases; Tumor Cells, Cultured; Tyrosine, Rattus
International Standard Serial Number (ISSN)
Article - Journal
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01 Dec 2012