The membrane
phospholipid phosphatidylinositol 4, 5-bisphosphate [PI (4,5)P2] is a critical signal transducer in eukaryotic cells. However, the physiological roles of the type I
phosphatidylinositol phosphate kinases(PIPKIs) that synthesize PI(4,5) P2 are unknown. Here we show that the alpha
isozyme of PIPKI (PIPKIalpha) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKIalpha-deficient mast cells exhibit increased degranulation and
cytokine production after
Fc(epsilon)RI crosslinking. In vivo, PIPKIalpha-/- mice display enhanced passive cutaneous and systemic
anaphylaxis. Mechanistically, filamentous actin was diminished in PIPKIalpha-/- mast cells and enhanced degranulation observed in the absence of PIPKIa was phenocopied in wild type mast cells treated with
latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of
Fc(epsilon)RI with
lipid rafts and
Fc(epsilon)RI mediated activation of signaling
proteins is augmented in PIPKIalpha-/- mast cells. PIPKIalpha is thus a negative regulator of
Fc(epsilon)RI-mediated cellular responses and
anaphylaxis which functions by controlling the actin cytoskeleton and dynamics of
Fc(epsilon)RI signaling. Our results are thus the first genetic evidence that PIPKI
isoforms, and the pool of PI (4,5) P2 produced by each
isoform, may be functionally specialized.