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A correction to this article has been published: Nishida et al., J. Cell Biol. 171 (1) 177
Published 5 July 2005. doi:10.1083/jcb.200501111
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 115-126
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Article

Fc{varepsilon}RI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane



Keigo Nishida1,2, Satoru Yamasaki1, Yukitaka Ito1,3, Koki Kabu1,2, Kotaro Hattori4, Tohru Tezuka5, Hirofumi Nishizumi5, Daisuke Kitamura6, Ryo Goitsuka6, Raif S. Geha7, Tadashi Yamamoto5, Takeshi Yagi4, and Toshio Hirano1,2,3

1 Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology (RCAI), Kanagawa 230-0045, Japan
2 Laboratory of Developmental Immunology (C7), Graduate School of Medicine
3 Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
4 KOKORO-Biology Group and CREST, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
5 Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6 Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Chiba 278-0022, Japan
7 Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115

Correspondence to Toshio Hirano: hirano{at}molonc.med.osaka-u.ac.jp

The aggregation of high affinity IgE receptors (Fc{varepsilon} receptor I [Fc{varepsilon}RI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how Fc{varepsilon}RI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that Fc{varepsilon}RI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the Fc{varepsilon}RI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule–plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway.

K. Nishida and S. Yamasaki contributed equally to this paper.

Abbreviations used in this paper: BMMC, bone marrow–derived mast cell; Fc{varepsilon}RI, Fc{varepsilon} receptor I; Gab2, Grb2-associated binder 2; LAT, linker for the activation of T cells; SLP-76, SH2 domain–containing leukocyte protein of 76 kD.


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