The Phospholipase Cγ1-dependent Pathway of FcϵRI-mediated Mast Cell Activation Is Regulated Independently of Phosphatidylinositol 3-Kinase*

By C. Tkaczyk, M. Beaven, S. Brachman, D. Metcalfe, A. Gilfillan. Journal of Biological Chemistry, 2003

116 citations recorded by the source corpus.

Mast cell degranulation following FcϵRI aggregation is generally believed to be dependent on phosphatidylinositide 3-kinase (PI 3-kinase)-mediated phospholipase C (PLC)γ activation. Here we report evidence that the PLCγ1-dependent pathway of FcϵRI-mediated activation of mast cells is independent of PI 3-kinase activation. In primary cultures of human mast cells, FcϵRI aggregation induced a rapid translocation and phosphorylation of PLCγ1, and subsequent inositol trisphosphate (IP3) production, which preceded PI 3-kinase-related signals. In addition, although PI 3-kinase-mediated responses were completely inhibited by wortmannin, even at high concentrations, this PI 3-kinase inhibitor had no effect on parameters of FcϵRI-mediated PLCγ activation, and had little effect on the initial increase in intracellular calcium levels that correlated with PLCγ activation. Wortmannin, however, did produce a partial (∼50%) concentration-dependent inhibition of FcϵRI-mediated degranulation in human mast cells and a partial inhibition of the later calcium response at higher concentrations. Further studies, conducted in mast cells derived from the bone marrow of mice deficient in the p85α and p85β subunits of PI 3-kinase, also revealed no defects in FcϵRI-mediated PLCγ1 activation. These data are consistent with the conclusion that the PLCγ-dependent component of FcϵRI-mediated calcium flux leading to degranulation of mast cells is independent of PI 3-kinase. However, PI 3-kinase may contribute to the later phase of FcϵRI-mediated degranulation in human mast cells.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7f8de8f8ae964b6e14643bb7a33265f95d6190ba

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1. A. Gilfillan
2. C. Tkaczyk

Citations in the corpus

• Integrated signalling pathways for mast-cell activation (2006, background): “In human mast cells, however, despite membrane translocation of both isoforms and marked phosphorylation of PLCγ 1 , following antigen challenge, phosphory-lation of PLCγ 2 has been difficult to detec”