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Inhibition of mast cell degranulation by a chimeric toxin containing a novel phosphatidylinositol-3,4,5-triphosphate phosphatase.

ABSTRACT: It is well established that many cell functions are controlled by the PI-3K signaling pathway and the signaling lipid, phosphatidylinositol-3,4,5-triphosphate (PIP3). This is particularly true for mast cells which play a key regulatory role in allergy and inflammation through activation via high-affinity IgE receptors (Fc?RI) leading to activation of signaling cascades and subsequent release of histamine and other pro-inflammatory mediators. A pivotal component of this cascade is the activation of PI-3K and a rise in intracellular levels of PIP3. In this study, we developed a novel chimeric toxin that selectively binds to mast cells and which functions as a PIP3 phosphatase. Specifically, the chimeric toxin was composed of the Fc?RI binding region of IgE and the active subunit of the cytolethal distending toxin, CdtB, which we have recently demonstrated to function as a PIP3 phosphatase. We demonstrate that the chimeric toxin retains PIP3 phosphatase activity and selectively binds to mast cells. Moreover, the toxin is capable of altering intracellular levels of PIP3, block antigen-induced Akt phosphorylation and degranulation. These studies provide further evidence for the pivotal role of PIP3 in regulating mast cell activation and for this signaling lipid serving as a novel target for therapeutic intervention of mast cell-mediated disease. Moreover, these studies provide evidence for the utilization of CdtB as a novel therapeutic agent for targeting the PI-3K signaling pathway.

SUBMITTER: Shenker BJ

PROVIDER: S-EPMC2993869 | biostudies-literature | 2010 Nov-Dec

REPOSITORIES: biostudies-literature

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Inhibition of mast cell degranulation by a chimeric toxin containing a novel phosphatidylinositol-3,4,5-triphosphate phosphatase.

Shenker Bruce J BJ Boesze-Battaglia Kathleen K Zekavat Ali A Walker Lisa L Besack Dave D Ali Hydar H

Molecular immunology 20100921 1-3

It is well established that many cell functions are controlled by the PI-3K signaling pathway and the signaling lipid, phosphatidylinositol-3,4,5-triphosphate (PIP3). This is particularly true for mast cells which play a key regulatory role in allergy and inflammation through activation via high-affinity IgE receptors (FcɛRI) leading to activation of signaling cascades and subsequent release of histamine and other pro-inflammatory mediators. A pivotal component of this cascade is the activation ...[more]

PMID: 20863570

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Project description:BackgroundBMP-induced chemotaxis of mesenchymal progenitors is fundamental for vertebrate development, disease and tissue repair. BMP2 induces Smad and non-Smad signalling. Whereas signal transduction via Smads lead to transcriptional responses, non-Smad signalling induces both, transcriptional and immediate/early non-transcriptional responses. However, the molecular mechanisms by which BMP2 facilitates planar cell polarity, cortical actin rearrangements, lamellipodia formation and chemotaxis of mesenchymal progenitors are poorly understood. Our aim was to uncover the molecular mechanism by which BMP2 facilitates chemotaxis via the BMP2-dependent activation of PI3K and spatiotemporal control of PIP3 production important for actin rearrangements at the mesenchymal cell cytocortex.ResultsWe unveiled the molecular mechanism by which BMP2 induces non-Smad signalling by PI3K and the role of the second messenger PIP3 in BMP2-induced planar cell polarity, cortical actin reorganisation and lamellipodia formation. By using protein interaction studies, we identified the class Ia PI3K regulatory subunit p55γ to act as a specific and non-redundant binding partner for BMP receptor type II (BMPRII) in concert with the catalytic subunit p110α. We mapped the PI3K interaction to a region within the BMPRII kinase. Either BMP2 stimulation or increasing amounts of BMPRI facilitated p55γ association with BMPRII, but BMPRII kinase activity was not required for the interaction. We visualised BMP2-dependent PIP3 production via PI3K p55γ/p110α and were able to localise PIP3 to the leading edge of intact cells during the process of BMP2-induced planar cell polarity and actin dependent lamellipodia formation. Using mass spectrometry, we found the highly PIP3-sensitive PH-domain protein LL5β to act as a novel BMP2 effector in orchestrating cortical actin rearrangements. By use of live cell imaging we found that knock-down of p55γ or LL5β or pharmacological inhibition of PI3K impaired BMP2-induced migratory responses.ConclusionsOur results provide evidence for an important contribution of the BMP2-PI3K (p55γ/p110α)- PIP3-LL5β signalling axis in mesenchymal progenitor cell chemotaxis. We demonstrate molecular insights into BMP2-induced PI3K signalling on the level of actin reorganisation at the leading edge cytocortex. These findings are important to better understand BMP2-induced cytoskeletal reorganisation and chemotaxis of mesenchymal progenitors in different physiological or pathophysiological contexts.

Dataset Information

Inhibition of mast cell degranulation by a chimeric toxin containing a novel phosphatidylinositol-3,4,5-triphosphate phosphatase.

Publications

Inhibition of mast cell degranulation by a chimeric toxin containing a novel phosphatidylinositol-3,4,5-triphosphate phosphatase.

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