Phosphorylation of Syk activation loop tyrosines is essential Syk function: An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody
ABSTRACT 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 · 2.68 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 · 1.22 Impact Factor
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- "Src and Fyn are regulated by phosphorylation on two sites: one at tyrosine 416 which is activatory, and the other at tyrosine 527 which is inhibitory (reviewed by Hunter, 1987). Similar phosphorylation sites are found in other SFK members: activation of phosphorylation are at tyrosines 394 for Lck, at tyrosines 323 and 352 for Syk, and inhibition of phosphorylation are at tyrosines 505 for Lck, and at tyrosines 525 and 526 for Syk (Chow et al., 1993; Law et al., 1996; Deckert et al., 1998; Zhang et al., 2000; Rao et al., 2001). Activating phosphorylation often results from autophosphorylation (Chiang and Sefton, 2000; reviewed by Roskoski, 2004; reviewed by Roskoski, 2005). "
ABSTRACT: Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby might contribute to tau aggregation. Thus, understanding the regulation modes of tau phosphorylation is of high interest in determining the possible causes at the origin of the formation of tau aggregates in order to elaborate protection strategies to cope with these lesions in Alzheimer's disease. Among the possible and specific interventions that reverse tau phosphorylation is the inhibition of certain tau kinases. Here, we extensively reviewed tau protein kinases, their physiological roles and regulation, their involvement in tau phosphorylation and their relevance to AD. We also reviewed the most common inhibitory compounds acting on each tau kinase.Ageing research reviews 06/2012; 12(1):289-309. DOI:10.1016/j.arr.2012.06.003 · 7.63 Impact Factor