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J. Biol. Chem., Vol. 282, Issue 52, 37669-37677, December 28, 2007

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TOM1L1 Is a Lyn Substrate Involved in FcRI Signaling in Mast Cells^*

From the Receptors and Signal Transduction Section, Oral Infection and Immunity Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892

Protein-tyrosine kinase Lyn and Syk are critical for antigen-receptor-induced signal transduction in mast cells. To identify novel Lyn/Syk substrates, we screened an RBL-2H3 bacterial expression library for proteins that were tyrosine phosphorylated with baculoviral expressed Lyn or Syk. Five clones as potential Lyn substrates and eight clones as Syk substrates were identified including known substrates such as SLP-76, LAT, and -tubulin. A potential substrate of Lyn identified was the molecule TOM1L1, which has several domains thought to be important for membrane trafficking and protein-protein interactions. Because the function of TOM1L1 is unclear, the rat TOM1L1 full-length cDNA was isolated and used to express the protein in COS-1 and RBL-2H3 mast cells. In COS-1 cells, the co-transfection of TOM1L1 and Lyn, but not Syk, resulted in the tyrosine phosphorylation of TOM1L1. In RBL-2H3 mast cells, the overexpressed TOM1L1 was strongly tyrosine phosphorylated in non-stimulated cells, and this phosphorylation was enhanced by FcRI aggregation. By subcellular fractionation, wild-type TOM1L1 was mainly in the cytoplasm with a small fraction constitutively associated with the membrane; this association was markedly reduced in deletion mutants lacking several of the protein interaction domains. The overexpression of TOM1L1 enhanced antigen-induced tumor necrosis factor (TNF) generation and release. Both protein interaction domains (VHS and the coiled-coil domains) were required for the increased TNF release, but not the increased TNF generation. These results suggest that TOM1L1 is a novel protein involved in the FcRI signal transduction for the generation of cytokines.

Received for publication, June 22, 2007 , and in revised form, October 5, 2007.

^* This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. 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 Both authors contributed equally to this work.

² Present address: Gunma Institute for Allergy and Asthma, 3233-1 Shinozuka, Ohra-machi, Gunma 370-0615, Japan.

³ Present address: Dept. of Pediatrics, National Hospital Organization-Saga National Hospital, Hinode 1-20-1, Saga, Japan.

⁴ To whom correspondence should be addressed: RAST Section, OIIB, Bldg. 10, Rm. 1N106, NIDCR, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-5105; Fax: 301-480-8328; E-mail: rs53x{at}nih.gov.

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