 establishment of FcεRI reconstitution systems in murine mast cells. This system allows us to investigate the biological functions of the FcεRIβ chain in mast cells. Polymorphisms (I181L, V183L, and E237G) in the coding region of the FcεRIβ chain have been found to be associated with allergic disorders. However, reconstitution studies did not find any effects of these variants on mast cell effector functions (Donnadieu et al., [@B9]; Furumoto et al., [@B14]).

Interestingly, the ITAM sequence of the FcεRIβ chain is unique, differing from the consensus ITAM sequence. While the FcεRIγ chain ITAM (YTGLNTRSQETYETL) contains the consensus sequence (YxxL-x~7~-YxxL), the FcεRIβ chain ITAM (Y~219~EELHVY~225~SPIY~229~SEL) contains a third non-canonical tyrosine (Y225) between two canonical tyrosine residues (Y219 and Y229; Figure [4](#F4){ref-type="fig"}). A mutational analysis of these tyrosine residues in the ITAM (tyrosine replaced with phenylalanine, Y→F) performed by our group revealed novel functions of the FcεRIβ chain (Furumoto et al., [@B15]).

![**FcεRIβ chain ITAM sequence**. The FcεRIβ chain contains a non-canonical tyrosine residue at position 225, which is involved in the negative regulation for mast cell activation.](fimmu-03-00112-g004){#F4}

The N-terminal canonical tyrosine (Y219) in the FcεRIβ chain ITAM is essential for the modulation of the effects of the FcεRIβ chain because of its ability to associate with Lyn upon FcεRI engagement, whereas the other canonical tyrosine (Y229) is dispensable for the interaction of the FcεRIβ chain with Lyn. Mast cells (αβ~FYF~γ2) harboring mutations in Y219 and Y229 showed a reduction in degranulation and cytokine production when stimulated with antigen at sufficient concentration, triggering an optimal degranulation response. Under the same stimulation conditions, the additional introduction of mutation of the middle non-canonical tyrosine (Y225) in αβ~FYF~γ2 mast cells (αβ~FFF~γ2) unexpectedly resulted in a marked increase in cyto