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 signaling is triggered by ligand-induced heterodimerization of the IL-2R beta and gamma c subunits, which results in the activation of signaling intermediates that are associated with either IL-2R beta or gamma c. Previous mutagenesis studies of the IL-2R beta cytoplasmic tail demonstrated that the partially conserved box 1 and box 2 motifs and specific tyrosine residues are critical for growth signaling. By deletion and alanine scanning mutagenesis, another set of residues that are critical for IL-2R-mediated signaling has now been identified. These residues lie within the divergent 35-amino acid "spacer" region separating box 1 and box 2. The role of this receptor subregion in early phases of IL-2R signaling was evaluated using BA/F3 stable cell lines expressing 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 phosphorylation, and Janus kinase activation were also markedly impaired. These findings indicate that this variable spacer region, which we have termed the V-box, is essential for the initiation of IL-2R-mediated signal transduction.
Liu
K D
KD
Gladstone Institute of Virology and Immunology, School of Medicine, University of California, San Francisco 94141, USA.
Lai
S Y
SY
Goldsmith
M A
MA
Greene
W C
WC
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000502:physiology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000737:chemistry* / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3