Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.

/pdf/lipid-rafts-and-signal-transduction-2pg659jt8g.pdf

Lipid rafts and signal transduction

The mast cell is a central player in allergy and asthma. Activation of these cells induces the release of preformed inflammatory mediators localized in specialized granules and the de novo synthesis and secretion of cytokines, chemokines, and eicosanoids. The balance of engaging inhibitory and activatory cell-surface receptors on mast cells determines whether the cell becomes active on encountering a challenge. However, recent evidence suggests that, once activated, a mast cell's response is further regulated by the balance of both positive and negative intracellular molecular events that extend well beyond the traditional role of kinases and phosphatases. These functional responses are also carefully governed by other protein and lipid mediators that determine the rate and extent of the response. Molecules that have adaptor functions, modulate lipids, and provide synergistic signals add to the regulatory complexity. Considerable information has been obtained from the study of the high-affinity receptor for IgE (FcɛRI), and thus it is the major focus of this review. The unifying theme is that the regulatory steps mentioned herein are required for promoting effective responses while protecting against unwanted inflammatory responses.

https://www.jacionline.org/article/S0091-6749(06)00863-3/pdf

Molecular regulation of mast cell activation

The aggregation of high affinity IgE receptors (Fcepsilon receptor I [FcepsilonRI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how FcepsilonRI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that FcepsilonRI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the FcepsilonRI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule-plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway.

/pdf/fceri-mediated-mast-cell-degranulation-requires-calcium-2bhhxylylt.pdf

FcεRI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane

Molecular adapters in FcεRI signaling and the allergic response

Regulation of phospholipase C gamma isoforms in haematopoietic cells: why one, not the other?

Cross-linking of the high-affinity IgE receptor (FceRI) on mast cells by IgE‐antigen complex triggers signal transduction cascades leading to the release of inflammatory mediators and production of cytokines, which are critical for the development of allergic reactions We have identified a novel member of the BASH/SLP-76 immunoreceptor-coupled adaptor family expressed in mast cells, termed MIST (for mast cell immunoreceptor signal transducer), which has later been found to be identical to a recently reported cytokine-dependent hemopoietic cell linker, Clnk Upon FceRI cross-linking, MIST/Clnk is tyrosine phosphorylated and associates with signaling proteins, phospholipase Cγ, Vav, Grb2 and linker for activation of T cells (LAT) Overexpression of a mutant form of MIST/Clnk inhibited FceRI-mediated degranulation, increase in intracellular Ca 2 , NF-AT

Yuri Hidaka

Papers

A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation