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Molecular and Cellular Biology, March 2000, p. 1759-1771, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Sequential Requirements of the N-Terminal Palmitoylation Site and SH2 Domain of Src Family Kinases in the Initiation and Progression of Fcepsilon RI Signaling

Zen-ichiro Honda,1,* Takeshi Suzuki,1 Hajime Kono,1 Masato Okada,2 Tadashi Yamamoto,3 Chisei Ra,4 Yutaka Morita,1 and Kazuhiko Yamamoto1

Department of Allergy and Rheumatology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655,1 Division of Protein Metabolism, Institute of Protein Research, Osaka University, Suita, Osaka,2 Institute of Medical Science, University of Tolyo, Shirokanedai, Minato-ku, Tokyo,3 and Department of Immunology, School of Medicine, Juntendo University, Bunkyo-ku Tokyo 113-8421,4 Japan

Received 7 June 1999/Returned for modification 8 July 1999/Accepted 10 November 1999

Initial biochemical signaling originating from high-affinity immunoglobulin E receptor (Fcvarepsilon RI) has been ascribed to Src family kinases. To understand the mechanisms by which individual kinases drive the signaling, we conducted reconstitution experiments: Fcvarepsilon RI signaling in RBL2H3 cells was first suppressed by a membrane-anchored, gain-of-function C-terminal Src kinase and then reconstructed with Src family kinases whose C-terminal negative regulatory sequence was replaced with a c-myc epitope. Those constructs derived from Lyn and Fyn, which are associated with detergent-resistant membranes (DRMs), physically interacted with resting Fcvarepsilon RI and reconstructed clustering-induced signaling that leads to calcium mobilization and ERK1 and -2 activation. c-Src-derived construct, which was excluded from DRMs, failed to interact with Fcvarepsilon RI and to restore the signaling, whereas creation of palmitoylatable Cys3 enabled it to interact with DRMs and with Fcvarepsilon RI and to restore the signaling. Deletion of Src homology 3 (SH3) domain from the Lyn-derived construct did not alter its ability to transduce the series of signaling. Deletion of SH2 domain did not affect its association with DRMs and with Fcvarepsilon RI nor clustering-induced tyrosine phosphorylation of Fcvarepsilon RI beta  and gamma  subunits, but it almost abrogated the next step of tyrosine phosphorylation of Syk and its recruitment to Fcvarepsilon RI. These findings suggest that Lyn and Fyn could, but c-Src could not, drive Fcvarepsilon RI signaling and that N-terminal palmitoylation and SH2 domain are required in sequence for the initial interaction with Fcvarepsilon RI and for the signal progression to the molecular assembly.

* Corresponding author. Mailing address: Department of Allergy and Rheumatology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 3-3815-5411. Fax: 3-3815-5954. E-mail: honda-phy{at}h.u-tokyo.ac.jp.

Molecular and Cellular Biology, March 2000, p. 1759-1771, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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