The Journal of Experimental Medicine
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Published online 14 March 2005 doi:10.1084/jem.20041891
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 6, 859-870
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ARTICLE

 Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I {alpha}

Junko Sasaki1,4,5, Takehiko Sasaki1,5,6,7, Masakazu Yamazaki1, Kunie Matsuoka2, Choji Taya2, Hiroshi Shitara2, Shunsuke Takasuga5,6, Miki Nishio4,5,6,7, Katsunori Mizuno1,5,6, Teiji Wada8, Hideyuki Miyazaki1, Hiroshi Watanabe1, Ryota Iizuka1,4,5, Shuichi Kubo2, Shigeo Murata3,7, Tomoki Chiba3, Tomohiko Maehama1, Koichi Hamada4, Hiroyuki Kishimoto4, Michael A. Frohman9, Keiji Tanaka3, Josef M. Penninger8, Hiromichi Yonekawa2, Akira Suzuki4, and Yasunori Kanaho1

1 Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
2 Department of Laboratory Animal Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
3 Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
4 Department of Molecular Biology, Akita University School of Medicine, Akita 010-8543, Japan
5 Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan
6 The 21st Century Center of Excellence Program, Akita University School of Medicine, Akita 010-8543, Japan
7 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
8 Institute of Molecular and Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria
9 Center for Developmental Genetics and Department of Pharmacology, State University of New York, Stony Brook, NY 11794

CORRESPONDENCE Takehiko Sasaki: tsasaki{at}med.akita-u.ac.jp OR Yasunori Kanaho: ykanaho{at}rinshoken.or.jp

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 largely unknown. Here, we show that the {alpha} isozyme of PIPKI (PIPKI{alpha}) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKI{alpha}-deficient mast cells exhibited increased degranulation and cytokine production after Fc{varepsilon} receptor-I cross-linking. In vivo, PIPKI{alpha}–/– mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKI{alpha}–/– mast cells, and enhanced degranulation observed in the absence of PIPKI{alpha} was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of Fc{varepsilon}RI with lipid rafts and Fc{varepsilon}RI-mediated activation of signaling proteins was augmented in PIPKI{alpha}–/– mast cells. Thus, PIPKI{alpha} is a negative regulator of Fc{varepsilon}RI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of Fc{varepsilon}RI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.

Abbreviations used: BMMC, bone marrow–derived mast cell; IP3, inositol 1,4,5-trisphosphate; LAT, linker for activation of T cells; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol 3, 4, 5-trisphosphate; PIPKI, type I phosphatidylinositol phosphate kinase; PIPKI{alpha}, {alpha} isozyme of PIPKI; PLC, phospholipase C; RBL, rat basophilic leukemia.

J. Sasaki and T. Sasaki contributed equally to this work.


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