The high affinity IgE Fc receptor (Fc epsilon RI) beta chain is well implicated as a signal amplifier through the immunoreceptor tyrosine-based activation motif (ITAM) in its C-terminal intracellular region. Our previous study, however, demonstrated that mutation in all of the three tyrosine residues within the Fc epsilon RI beta ITAM did not impair Fc epsilon RI-induced cytokine production, suggesting a possible functional region other than the ITAM. To investigate the ITAM-independent mechanism by which Fc epsilon RI beta regulates Fc epsilon RI-induced cytokine production, mouse mast cells expressing various Fc epsilon RI beta mutants were generated. We observed that truncation of the Fc epsilon RI beta C-terminus downstream of the ITAM resulted in a considerable decrease in Fc epsilon RI-induced IL-6 production but not degranulation. Furthermore, mutagenesis of a single C-terminal aspartic acid (D234) to alanine (beta-D234A) also significantly impaired IL-6 production. In addition, the similarity between the circular dichroism (CD) spectra of the wild type and beta-D234A suggests that the secondary structure of the Fc epsilon RI beta C-terminus was not affected by the D234A mutation. Consistently, we did not observe any effect of this mutation on Fc epsilon RI-induced tyrosine phosphorylation of Fc epsilon RI beta. These observations strongly suggest a novel signaling pathway mediated by the cytoplasmic tail downstream of the Fc epsilon RI beta ITAM. (C) 2011 Elsevier Inc. All rights reserved.