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Molecular and Cellular Biology, June 2007, p. 4406-4415, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.02109-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

LAT and NTAL Mediate Immunoglobulin E-Induced Sustained Extracellular Signal-Regulated Kinase Activation Critical for Mast Cell Survival{triangledown}

Sho Yamasaki,1 Eri Ishikawa,1 Machie Sakuma,1 Osami Kanagawa,2 Alec M. Cheng,3 Bernard Malissen,4 and Takashi Saito1*

Laboratory for Cell Signaling,1 Laboratory for Autoimmune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan,2 Center for Immunology, Washington University School of Medicine, St. Louis, Missouri,3 Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, Marseille, France4

Received 10 November 2006/ Returned for modification 14 December 2006/ Accepted 30 March 2007

Immunoglobulin E (IgE) induces mast cell survival in the absence of antigen (Ag) through the high-affinity IgE receptor, Fc{varepsilon} receptor I (Fc{varepsilon}RI). Although we have shown that protein tyrosine kinase Syk and sustained extracellular signal-regulated kinase (Erk) activation are required for IgE-induced mast cell survival, how Syk couples with sustained Erk activation is still unclear. Here, we report that the transmembrane adaptors LAT and NTAL are phosphorylated slowly upon IgE stimulation and that sustained but not transient Erk activation induced by IgE was inhibited in LAT–/– NTAL–/– bone marrow-derived mast cells (BMMCs). IgE-induced survival requires Ras activation, and both were impaired in LAT–/– NTAL–/– BMMCs. Sos was preferentially required for Fc{varepsilon}RI signals by IgE rather than IgE plus Ag. Survival impaired in LAT–/– NTAL–/– BMMCs was restored to levels comparable to those of the wild type by membrane-targeted Sos, which bypasses the Grb2-mediated membrane recruitment of Sos. The IgE-induced survival of BMMCs lacking Gads, an adaptor critical for the formation of the LAT-SLP-76-phospholipase C{gamma} (PLC{gamma}) complex, was observed to be normal. IgE stimulation induced the membrane retention of Grb2-green fluorescent protein fusion proteins in wild-type but not LAT–/– NTAL–/– BMMCs. These results suggest that LAT and NTAL contribute to the maintenance of Erk activation and survival through the membrane retention of the Ras-activating complex Grb2-Sos and, further, that the LAT-Gads-SLP-76-PLC{gamma} and LAT/NTAL-Grb2-Sos pathways are differentially required for degranulation and survival, respectively.

* Corresponding author. Mailing address: 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Phone: 81-45-503-7037. Fax: 81-45-503-7036. E-mail: saito{at}rcai.riken.jp

{triangledown} Published ahead of print on 9 April 2007.

Molecular and Cellular Biology, June 2007, p. 4406-4415, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.02109-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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