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Volume 272, Number 41, Issue of October 10, 1997 pp. 25753-25760
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Roles of C-terminal Src Kinase in the Initiation and the Termination of the High Affinity IgE Receptor-mediated Signaling

(Received for publication, January 30, 1997, and in revised form, July 8, 1997)

Zen-ichiro Honda , Takeshi Suzuki , Naoto Hirose , Makoto Aihara ^§ , Takao Shimizu ^§ , Shigeyuki Nada ^¶ , Masato Okada ^¶ , Chisei Ra , Yutaka Morita and Koji Ito

From the Departments of Internal Medicine and Physical Therapy and of ^§ Biochemistry, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan, the ^¶ Division of Protein Metabolism, Institute of Protein Research, Osaka University, Suita, Osaka 565, Japan, and the  Department of Immunology, Juntendo University, School of Medicine, 2-1-1, Hongo Bunkyo-ku Tokyo 113, Japan

As an attempt to analyze the roles of C-terminal Src kinase (Csk) in the high affinity IgE receptor (FcRI)-mediated signaling, we overexpressed Csk, a membrane-targeted form of Csk (mCsk), and a kinase-defective, membrane-targeted form of Csk (mCsk()) in rat basophil leukemia (RBL) 2H3 cells. Specific activity of Lyn at the basal state was decreased in Csk-expressing cells, and further decreased in mCsk-expressing cells. In mCsk()-expressing cells, basal specific activity of Lyn was increased, thereby indicating that mCsk() functioned as a dominant negative molecule. The onset of FcRI-mediated Lyn activation was delayed in Csk-expressing cells, and further delayed in mCsk-expressing cells. In mCsk()-expressing cells, Lyn activation was rapid and quite long lasting. These findings indicate (i) Csk negatively regulates rapid FcRI/Lyn coupling, and (ii) Csk activity is potentially required for its termination. The onsets of the series of events including tyrosyl phosphorylation of Syk, mitogen-activated protein (MAP) kinase activation, elevation of intracellular calcium concentration ([Ca²⁺]_i), and histamine release were all stepwisely delayed in Csk-expressing cells and in mCsk-expressing cells. The durations of Syk phosphorylation and MAP kinase activation also closely correlated with those of Lyn activation, but [Ca²⁺]_i elevation and histamine release followed different temporal patterns: the delayed responses in Csk-expressing cells and in mCsk-expressing cells led to sustained [Ca²⁺]_i oscillation and histamine release, while the prompt responses in parent cells and mCsk()-expressing cells rapidly subsided. These findings provide further evidence that the initiations of the FcRI-mediated signals are upstreamly regulated by Src family protein tyrosine kinases and revealed that their terminations are regulated by Lyn-dependent (Syk and MAP kinase) and -independent ([Ca²⁺]_i elevation and histamine release) mechanisms.

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