Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I {alpha}.
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.
Sasaki
Junko
J
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
Sasaki
Takehiko
T
Yamazaki
Masakazu
M
Matsuoka
Kunie
K
Taya
Choji
C
Shitara
Hiroshi
H
Takasuga
Shunsuke
S
Nishio
Miki
M
Mizuno
Katsunori
K
Wada
Teiji
T
Miyazaki
Hideyuki
H
Watanabe
Hiroshi
H
Iizuka
Ryota
R
Kubo
Shuichi
S
Murata
Shigeo
S
Chiba
Tomoki
T
Maehama
Tomohiko
T
Hamada
Koichi
K
Kishimoto
Hiroyuki
H
Frohman
Michael A
MA
Tanaka
Keiji
K
Penninger
Josef M
JM
Yonekawa
Hiromichi
H
Suzuki
Akira
A
Kanaho
Yasunori
Y
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
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