Associate editor: P.S. FosterMast cell function: Regulation of degranulation by serine/threonine phosphatases
Introduction
Mast cells, which are derived from haematopoetic stem cells, are key effector cells in allergic reactions and IgE associated immune responses. They are also implicated as regulators of adaptive immune responses and this immunoregulatory role has been suggested to be potentially more important than the better established effector role. Attention has therefore begun to re-focus on the mast cell as a potential therapeutic target for asthma and related disorders (Bradding, 2003, Brightling et al., 2003). Mast cells secrete a large number of mediators in response to a diverse range of stimuli with the majority being secreted by regulated exocytosis degranulation (Blank & Rivera, 2004). While significant advances have been made in understanding the basic mechanisms of exocytosis, the key regulatory steps in mast cell degranulation remain unknown. In this review the molecular mechanisms of mast cell degranulation will be reviewed with emphasis on the role of serine/threonine protein phosphatases which we suggest have the potential to be novel targets for the design of new drugs that regulate the degranulation process.
Section snippets
Mast cells and asthma
Asthma is a major cause of morbidity and mortality and its prevalence continues to rise (Cantani & Micera, 2005, Butland et al., 2006). At the cellular level, asthma involves a complex interplay between a variety of cell types including mast cells, basophils, eosinophils, neutrophils and lymphocytes with associated increased production of chemokines and cytokines. The precise role(s) played by each cell type and their relative importance in the pleiotropic presentation of asthma and related
General mechanisms of exocytosis
Mast cells secrete a wide range of intragranular mediators by the process of exocytosis, which utilises much of the same conserved basic molecular machinery that drives membrane trafficking in most cells (Blank & Rivera, 2004). Common proteins that are involved in the basic exocytotic machinery include the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family of proteins which are found on both vesicular and plasma membranes and form stable fusion (‘core’)
Classification of protein phosphatases
Whilst the human genome encodes for approximately 500 protein kinases, only 4 distinct families of protein phosphatase with around 150 individual members account for the dephosphorylation process (Cohen, 2002). Of these 150, more than 2/3 of the members, belong to the protein tyrosine phosphatase (PTP) family (Tautz et al., 2006) with only 40 members being responsible for the specific dephosphorylation of serine and threonine residues (Cohen, 2002). The PTP family of protein phosphatase also
Regulation of the phosphoprotein phosphatase family
Clearly, a relatively small number of serine/threonine phosphatases is responsible for dephosphorylating a vast array of proteins that have been phosphorylated by any one or several of a much larger number of protein kinases. Although historically the view of protein phosphatases as relatively non-specific and uncontrolled has been held, it is now clear that specific changes in substrate phosphorylation levels are regulated at both kinase and phosphatase levels. To specifically regulate cell
Serine/threonine phosphatases in mast cell degranulation
The majority of evidence suggesting a role for serine/threonine phosphatases in regulating mast cell degranulation has arisen from the use of the marine toxin, okadaic acid. Okadaic acid inhibits all PPP family phosphatases, with a degree of selectivity for the PPP2/4/6 family (Hastie & Cohen, 1998). However, differential sensitivity in vitro is of limited value in vivo where the concentrations of PPP family members is in the high nanomolar to low micromolar range and therefore requires
Protein phosphatases in mediator synthesis
Whilst it is clear that protein phosphatases regulate exocytosis in a variety of cell types (Sim et al., 2003), measurements of exocytosis must also take into account the rate of synthesis and accumulation of granule contents prior to release. Indeed in adrenal chromaffin cells, okadaic acid appears to increase exocytosis but this is due to increased uptake of catecholamine into secretory granules (Machado et al., 2001). Activation of mast cells also stimulates the production of several
Conclusions and future perspectives
Renewed interest in mast cells as key effector and modulator cells in a variety of physiological processes and diseased states has heightened the importance of understanding the molecular events underlying mast cell degranulation. A dynamic molecular architecture is required to promote the action of a vast array of signals that all result in the movement of secretory granules through the cytoskeletal barrier to fuse with the plasma membrane and release their contents. A range of protein–protein
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The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil
2016, International ImmunopharmacologyCitation Excerpt :It is the phosphorylation of target proteins (such as myosin) on the cell membrane by PKC that initiates the process of secretion. PP2A, which regulates PKC activity in this respect, has been identified as a key enzyme in the regulation of mast cell reactivity and treatment of mast cells with okadaic acid inhibits secretion of mediators [26]. In this study PP2A translocation and activity was assessed indirectly in mast cells by monitoring the length of time that PKC is resident at the membrane following cell activation.
Increased corticosteroid sensitivity by a long acting β <inf>2</inf> agonist formoterol via β <inf>2</inf> adrenoceptor independent protein phosphatase 2A activation
2012, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :PP2A is known to play roles in cell signal transduction and in many cellular functions [25], and we previously found that PP2A activity and protein expression were reduced in PBMCs obtained from severe asthma patients. PP2A catalytic subunit provides a central focus for the regulation of PP2A complexes and activity [26]. PP2A catalytic subunit has 2 isoforms (α and β) and the α isoform is 10 times more abundant than the β isoform [27].
Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation
2010, Cellular SignallingCitation Excerpt :Whilst the early phosphorylation events following FcεRI receptor activation are well understood [9], there is little understanding of the dephosphorylation events that regulate secretory granule mobilisation and fusion. Serine/threonine phosphorylation is an integral process in degranulation events [10–12] and previous studies have attempted to identify the protein phosphatases involved (reviewed in [13]). The majority of studies have relied upon broad based pharmacological inhibitors and generally correlate the inhibition of serine/threonine protein phosphatases with the inhibition of secretion.
Vitamin E: The shrew waiting to be tamed
2009, Free Radical Biology and MedicineModulation of signal transduction by vitamin E
2007, Molecular Aspects of MedicineVitamin E and Mast Cells
2007, Vitamins and HormonesCitation Excerpt :Other events influenced by signal transduction enzymes such as secretion of inflammatory cytokines and proteases, migration, or modulation of differentiation and survival could also be affected by vitamin E. Several studies have shown that vitamin E inhibits PKC activity via activation of PP2A leading to dephosphorylation of PKC (Egger et al., 2003; Neuzil et al., 2001; Ricciarelli et al., 1998). Interestingly, serine/threonine phosphatases and in particular PP2A play an important role in mast cell degranulation (reviewed in Sim et al., 2006), and it remains to be shown whether vitamin E can affect the degranulation process via activation of PP2A or via inhibition of PKC and PKB activity. Degranulation and cytokine production are promoted in synergy by SCF via c‐kit receptor and by antigen exposure via FcεRI, leading to activation of phospholipase Cγ, calcium mobilization, activation of several PKC isoforms, mitogen‐activated protein kinases (MAPK), and the PI3K/PKB signal transduction pathway (Hundley et al., 2004; Seebeck et al., 2001).