Mobile cell surface receptors allow a cell to sense its environment and respond to it. For many receptors signaling is initiated when receptorsare aggregated. Receptoraggregation is brought about when multivalent ligands bridge two or more receptorsor when receptorson one cell bind to ligands onanother cell causing the accumulation of receptorsin the contact region. Aggregation of receptors is rapidly followed by phosphorylation of sites on the cytoplasmic domains of the receptors as well as on other proteins. Some of these sites become binding sites for other signaling molecules, which can lead to the formation of large protein complexes, while other sites of phosphorylation regulate protein function. Because proteins can be modified at multiple sites and can combine in multiple ways, the number of possible distinct protein complexes that may participate in a cell signaling cascade can be huge ? a phenomenon called combinational complexity. We have created software that can automatically handle combinatorial complexity and used it to build a detailed model of the initial signaling events mediated by FctRI, a key receptor in allergic reactions. This model contains the reactions involving a bivalent ligand, FcsRI,two kinases, Lyn and Syk, and a pool of phosphatases. The model predicts how the expression levels of these proteins affect the strength of signaling, enabling comparisonwith clinical data on the levels of protein expression invarious effector cells. Building on this work we will extend the model, adding the kinases, Fyn,which associates with FcERI, and Csk, which regulates the activity of Lyn and Fyn, as well as Csk-binding protein, a Lyn substrate that regulates Csk. In addition we will add LAT, Grb2 and Sos1, which form extended complexes posing a major computational challenge. Working closely with experimental collaborators we will add additional components as needed. The models we develop serve to rigorously test ideas about biological mechanisms, aid in analyzing experiments, determine parameter values, suggest new experiments and identifiy possible sites for therapeutic intervention. With the experience we have gained from modeling FceRI signaling we will build mechanistic models of two other Fc receptors, FcyRllb which, when co-crosslinked with FceRI, acts as an inhibitory receptor and FcyRllla, the receptor on Natural Killer cells that mediates antibody-dependent cell-mediated cytotoxicity. The work we propose is health related, bearing on allergic disease and on the mode of action of monoclonal antibodies and immunoadhesinsthat are used as drugs to target tumor cells and cells driving autoimmune diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Marino, Pamela
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Los Alamos National Lab
Los Alamos
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