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Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1¹

Kazuko Nakata^*, Tetsuro Yoshimaru, Yoshihiro Suzuki, Toshio Inoue, Chisei Ra, Hidetaka Yakura^2,* and Kazuya Mizuno^3,*

^* Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Science, Fuchu, Tokyo, Japan and Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Sciences, Itabashi-Ku, Tokyo, Japan

Src homology region 2 domain-containing phosphatase 1 (SHP-1), a cytoplasmic protein tyrosine phosphatase, plays an important role for the regulation of signaling from various hematopoietic cell receptors. Although SHP-1 is shown to be a negative signal modulator in mast cells, its precise molecular mechanisms are not well defined. To elucidate how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, FcRI. Upon FcRI ligation, motheaten-derived bone marrow-derived mast cells showed enhanced tyrosine phosphorylation of Src homology region 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and linker for activation of T cells, activation of mitogen-activated protein kinases and gene transcription and production of cytokine. Because the activity of Syk, responsible for the phosphorylation of SLP-76 and linker for activation of T cells, is comparable irrespective of SHP-1, both molecules might be substrates of SHP-1 in mast cells. Interestingly, the absence of SHP-1 expression disrupted the association between SLP-76 and phospholipase C, which resulted in the decreased phospholipase C phosphorylation, calcium mobilization, and degranulation. Collectively, these results suggest that SHP-1 regulates FcRI-induced downstream signaling events both negatively and positively by functioning as a protein tyrosine phosphatase and as an adaptor protein contributing to the formation of signaling complex, respectively.

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 in part by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid High-Tech Research Center Project (2002–2006) for Private Universities matching fund subsidy from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

² Current address: Université Paris 1 Panthéon-Sorbonne, 17 rue de la Sorbonne, Paris, France.

³ Address correspondence and reprint requests to Dr. Kazuya Mizuno, Department of Immunology and Signal Transduction, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Science, 2-6 Musashidai, Fuchu, Tokyo, Japan. E-mail address: kzmizuno{at}tmin.ac.jp

⁴ Abbreviations used in this paper: FcRI, high affinity IgE receptor; PTK, protein tyrosine kinase; SH2, Src homology region 2; PLC, phospholipase C; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; LAT, linker for activation of T cell; PTP, protein tyrosine phosphatase; SHP-1, SH2 domain-containing phosphatase 1; me, motheaten; BMMC, bone marrow-derived mast cells; WT, wild type; PY, phosphotyrosine; HSA, human serum albumin; TCL, total cell lysates; TG, thapsigargin; CRAC, Ca²⁺ release-activated Ca²⁺; STIM1, stromal interacting molecule 1; ER, endoplasmic reticulum.

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