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RhoH Plays Critical Roles in FcRI-Dependent Signal Transduction in Mast Cells¹

Hiroyo Oda^*, Manabu Fujimoto, Michael S. Patrick^*,, Dai Chida^*, Yoshinori Sato^*, Yoshinao Azuma, Hiroki Aoki, Takaya Abe^¶, Harumi Suzuki^2,* and Mutsunori Shirai

^* Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan; Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Microbiology, Yamaguchi University School of Medicine, Ube, Japan; Cardiovascular Research Institute Kurume University School of Medicine, Kurume, Japan; and ^¶ Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN Kobe, Japan

RhoH is an atypical small G protein with defective GTPase activity that is specifically expressed in hematopoietic lineage cells. RhoH has been implicated in regulation of several physiological processes including hematopoiesis, integrin activation, and T cell differentiation and activation. In the present study, we investigated the role of RhoH in mast cells by generating RhoH knockout mice. Despite observing normal development of mast cells in vivo, passive systemic anaphylaxis and histamine release were impaired in these mice. We also observed defective degranulation and cytokine production upon FcRI ligation in RhoH-deficient bone marrow-derived mast cells. Furthermore, FcRI-dependent activation of Syk and phosphorylation of its downstream targets, including LAT, SLP76, PLC1, and PLC2 were impaired, however phosphorylation of the -subunit of FcRI remained intact. We also found RhoH-Syk association that was greatly enhanced by active Fyn. Our results indicate that RhoH regulates FcRI signaling in mast cells by facilitating Syk activation, possibly as an adaptor molecule for Syk.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology.

² Address correspondence and reprint requests to Dr. Harumi Suzuki, Department of Pathology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku, Tokyo, Japan. E-mail address: hsuzuki{at}ri.imcj.go.jp

³ Abbreviations used in this paper: PSA, passive systemic anaphylaxis; BMMC, bone marrow-derived mast cell; HSA, human serum albumin; HA, hemagglutinin.