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J. Biol. Chem., Vol. 280, Issue 48, 40261-40270, December 2, 2005

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Btk Plays a Crucial Role in the Amplification of FcRI-mediated Mast Cell Activation by Kit^*

Shoko Iwaki1, Christine Tkaczyk, Anne B. Satterthwaite2, Kristina Halcomb, Michael A. Beaven¶, Dean D. Metcalfe, and Alasdair M. Gilfillan3

From the Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1881, the Department of Internal Medicine and Center for Immunology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8884, and the ^¶Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1760

Stem cell factor (SCF) acts in synergy with antigen to enhance the calcium signal, degranulation, activation of transcription factors, and cytokine production in human mast cells. However, the underlying mechanisms for this synergy remain unclear. Here we show, utilizing bone marrow-derived mast cells (BMMCs) from Btk and Lyn knock-out mice, that activation of Btk via Lyn plays a key role in promoting synergy. As in human mast cells, SCF enhanced degranulation and cytokine production in BMMCs. In Btk^-/- BMMCs, in which there was a partial reduction in the capacity to degranulate in response to antigen, SCF was unable to enhance the residual antigen-mediated degranulation. Furthermore, as with antigen, the ability of SCF to promote cytokine production was abrogated in the Btk^-/- BMMCs. The impairment of responses in Btk^-/- cells correlated with an inability of SCF to augment phospholipase C₁ activation and calcium mobilization, and to phosphorylate NFB and NFAT for cytokine gene transcription in these cells. Similar studies with Lyn^-/- and Btk^-/-/Lyn^-/- BMMCs indicated that Lyn was a regulator of Btk for these responses. These data demonstrate, for the first time, that Btk is a key regulator of a Kit-mediated amplification pathway that augments FcRI-mediated mast cell activation.

Received for publication, June 3, 2005 , and in revised form, August 24, 2005.

^* This work was supported in part by the NIAID Intramural Program of the National Institutes of Health. 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 Supported by a Japan Society for the Promotion of Science research fellowship for Japanese Biomedical and Behavioral Research at National Institutes of Health.

² Southwestern Medical Foundation Scholar in Biomedical Research.

³ To whom correspondence should be addressed: Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bldg. 10, Rm. 11C206, 10 Center Dr., MSC 1881, Bethesda, MD 20892-1881. Tel.: 301-496-8757; Fax: 301-480-8384; E-mail: agilfillan{at}niaid.nih.gov.

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