IDENTIFICATION OF A VARIABLE REGION WITHIN THE CYTOPLASMIC TAIL OF THE IL-2 RECEPTOR BETA-CHAIN THAT IS REQUIRED FOR GROWTH SIGNAL-TRANSDUCTION

Interleukin-2 (IL-2) regulates numerous biological events, including T lymphocyte proliferation. Interleukin-2 receptor (IL-2R)-mediated sig naling is triggered by ligand-induced heterodimerization of the IL-2R beta and gamma(c) subunits, which results in the activation of signali ng intermediates that are associated with either IL-2R beta or gamma(c ). Previous mutagenesis studies of the IL-2R beta cytoplasmic tail dem onstrated that the partially conserved box 1 and box 2 motifs and spec ific tyrosine residues are critical for growth signaling. By deletion and alanine scanning mutagenesis, another set of residues that are cri tical for IL-2R-mediated signaling has now been identified. These resi dues lie within the divergent 35-amino acid ''spacer'' region separati ng box 1 and box 2. The role of this receptor subregion in early phase s of IL-2R signaling was evaluated using BA/F3 stable cell lines expre ssing three functionally impaired mutants from this region. All three cell lines displayed substantially diminished growth responsiveness to IL-2. Receptor-mediated STAT factor activation, IL-2R beta phosphoryl ation, and Janus kinase activation were also markedly impaired. These findings indicate that this variable spacer region, which we have term ed the V-box, is essential for the initiation of IL-2R-mediated signal transduction.