Phosphorylation of Syk activation loop tyrosines is essential Syk function: An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody
Receptors and Signal Transduction Section, Oral Infection and Immunity Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.Journal of Biological Chemistry (Impact Factor: 4.57). 12/2000; 275(45):35442-7. DOI: 10.1074/jbc.M004549200
Syk is an important protein-tyrosine kinase in immunoreceptor signaling. FcepsilonRI aggregation in mast cells induces tyrosine phosphorylation and increased enzymatic activity of Syk. The two adjacent tyrosines in the Syk activation loop are thought to be important for the propagation of FcepsilonRI signaling. To evaluate the phosphorylation of these tyrosines in vivo and further understand the relationship of Syk tyrosine phosphorylation with its function, an antibody was developed specific for phosphorylated tyrosines in the activation loop of Syk. FcepsilonRI aggregation on mast cells induced the phosphorylation of both tyrosine residues of the activation loop. The kinase activity of Syk played the major role in phosphorylating its activation loop tyrosines both in vivo and in vitro. In FcepsilonRI-stimulated mast cells, the total Syk tyrosine phosphorylation paralleled the phosphorylation of its activation loop tyrosines and downstream propagation of signals for histamine release. In contrast, the cell surface binding of anti-ganglioside monoclonal antibody AA4 induced only strong general tyrosine phosphorylation of Syk and minimal histamine release and weak phosphorylation of activation loop tyrosines. These results demonstrate that phosphorylation of the activation loop tyrosines is important for mediating receptor signaling and is a better marker of Syk function than is total Syk tyrosine phosphorylation.
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- "SYK is associated with the γ chain of the FcεRI. Binding of SYK to phosphorylated γ chain ITAM through the SYK SH2 domains induces a conformational change in the kinase, leading to its increased enzymatic activity (Zhang et al., 2000; Siraganian et al., 2010). Tec family kinases represent another class of non-receptor protein tyrosine kinases that are implicated in FcεRI-mediated activation. "
ABSTRACT: Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic inflammation that causes asthma, allergic rhinitis, food allergy and atopic dermatitis. Mast cells are usually increased in inflammatory sites of allergy and, upon activation, release various chemical, lipid, peptide and protein mediators of allergic reactions. Since antigen/immunoglobulin E (IgE)-mediated activation of these cells is a central event to trigger allergic reactions, innumerable studies have been conducted on how these cells are activated through cross-linking of the high-affinity IgE receptor (FcεRI). Development of mature mast cells from their progenitor cells is under the influence of several growth factors, of which the stem cell factor (SCF) seems to be the most important. Therefore, how SCF induces mast cell development and activation via its receptor, KIT, has been studied extensively, including a cross-talk between KIT and FcεRI signaling pathways. Although our understanding of the signaling mechanisms of the FcεRI and KIT pathways is far from complete, pharmaceutical applications of the knowledge about these pathways are underway. This review will focus on recent progresses in FcεRI and KIT signaling and chemotaxis. Copyright © 2015. Published by Elsevier B.V.European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.02.057 · 2.53 Impact Factor
- "FcεRI signaling relies on Lyn-dependent phosphorylation of ITAMs on the cytoplasmic portion of the β and γ receptor subunits. The protein kinase Syk is recruited to the phosphorylated ITAMs where it becomes activated and autophosphorylated (Zhang et al. 2000; de Castro et al. 2010 "
Article: Mast Cell Function[Show abstract] [Hide abstract]
ABSTRACT: Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 07/2014; 62(10). DOI:10.1369/0022155414545334 · 1.39 Impact Factor
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- "These two rules differ in whether Syk is phosphorylated at its activation loop tyrosine residues Y519 and Y520, which are treated as a single site for simplicity. Phosphorylation of the activation loop enhances the catalytic activity of Syk (48). Rate constants consistent with this regulatory mechanism are given after each rule, and are assigned values in the “parameters” block of the model specification (File S1 in Supplementary Material). "
ABSTRACT: Antigen receptors play a central role in adaptive immune responses. Although the molecular networks associated with these receptors have been extensively studied, we currently lack a systems-level understanding of how combinations of non-covalent interactions and post-translational modifications are regulated during signaling to impact cellular decision-making. To fill this knowledge gap, it will be necessary to formalize and piece together information about individual molecular mechanisms to form large-scale computational models of signaling networks. To this end, we have developed an interaction library for signaling by the high-affinity IgE receptor, FcεRI. The library consists of executable rules for protein-protein and protein-lipid interactions. This library extends earlier models for FcεRI signaling and introduces new interactions that have not previously been considered in a model. Thus, this interaction library is a toolkit with which existing models can be expanded and from which new models can be built. As an example, we present models of branching pathways from the adaptor protein Lat, which influence production of the phospholipid PIP3 at the plasma membrane and the soluble second messenger IP3. We find that inclusion of a positive feedback loop gives rise to a bistable switch, which may ensure robust responses to stimulation above a threshold level. In addition, the library is visualized to facilitate understanding of network circuitry and identification of network motifs.Frontiers in Immunology 04/2014; 5:172. DOI:10.3389/fimmu.2014.00172
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