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Original Article

^a Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
^b National Research Institute of Vegetables, Ornamental Plants, and Tea, Shizuoka 428-8501, Japan
^c Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
Division of Allergy, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121.858-558-3526858-558-3500

toshi_kawakami{at}liai.org

Cross-linking of FcRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)- promoters. Transcription from the nuclear factor B (NF-B), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IB-, a cytoplasmic protein that binds NF-B and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3β, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF- in FcRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-B, NF-AT, and AP-1 that contributes to the production of cytokines.

Key Words: FcRI • Lyn • Btk • NF-B • signal transduction

Abbreviations used in this paper: AP-1, activator protein 1; BMMC, bone marrow–derived mast cell; Btk, Bruton's tyrosine kinase; DN, dominant negative; ERK, extracellular signal–regulated kinase; GSK, glycogen synthase kinase; HA, hemagglutinin; HSA, human serum albumin; IKK, IB kinase; ITAM, immunoreceptor tyrosine-based activation motif; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MEKK, MEK kinase; NF-B, nuclear factor B; PDK, 3-phosphoinositide–dependent kinase; PH, pleckstrin homology; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTK, protein tyrosine kinase; RBL, rat basophilic leukemia; SCF, stem cell factor; SH, Src homology; wt, wild-type.

© 2000 The Rockefeller University Press

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