title: Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I {alpha}.
abstract: The membrane phospholipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P(2)] 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)P(2) are largely 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 exhibited increased degranulation and cytokine production after Fcepsilon receptor-I cross-linking. In vivo, PIPKIalpha(-/-) mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKIalpha(-/-) mast cells, and enhanced degranulation observed in the absence of PIPKIalpha was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of FcepsilonRI with lipid rafts and FcepsilonRI-mediated activation of signaling proteins was augmented in PIPKIalpha(-/-) mast cells. Thus, PIPKIalpha is a negative regulator of FcepsilonRI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of FcepsilonRI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.
authors.affiliation: Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Kunie
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takasuga
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.forename: Katsunori
authors.initials: K
authors.lastname: Mizuno
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Ryota
authors.initials: R
authors.lastname: Iizuka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kubo
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murata
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Maehama
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
mesh_terms: D000199:Actins / Q000378:metabolism; D000707:Anaphylaxis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D015550:Cell Degranulation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000199:Actins; D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D017455:Receptors, IgE; D013844:Thiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase