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The amino terminus of JAK3 is necessary and sufficient for binding to the common γ chain and confers the ability to transmit interleukin 2-mediated signals

1997; National Academy of Sciences; Volume: 94; Issue: 13 Linguagem: Inglês

10.1073/pnas.94.13.6910

1091-6490

Min Chen, Alan Cheng, Yi-Qing Chen, Anka Hymel, Eric P. Hanson, Lida Kimmel, Yasuhiro Minami, Tadatsugu Taniguchi, Paul S. Changelian, John J. O’Shea,

interferon and immune responses

JAK3 is a protein tyrosine kinase that specifically associates with the common γ chain (γ c ), a shared subunit of receptors for interleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or γ c presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3–γ c interaction. Despite the key roles of JAK3 and γ c in lymphocytic development and function, the molecular basis of this interaction remains poorly understood. In this study, we have characterized the regions of JAK3 involved in γ c association. By developing a number of chimeric JAK3–JAK2 constructs, we show that the binding specificity to γ c can be conferred to JAK2 by transferring the N-terminal domains of JAK3. Moreover, those JAK3–JAK2 chimeras capable of binding γ c were also capable of reconstituting IL-2 signaling as measured by inducible phosphorylation of the chimeric JAK3–JAK2 protein, JAK1, the IL-2 receptor β chain, and signal transducer and activator of transcription 5A. Subsequent deletion analyses of JAK3 have identified the N-terminal JH7-6 domains as a minimal region sufficient for γ c association. Furthermore, expression of the mutant containing only the JH7-6 domains effectively competed with full-length JAK3 for binding to γ c . We conclude that the JH7-6 domains of JAK3 are necessary and sufficient for γ c association. These studies offer clues toward a broader understanding of JAK-mediated cytokine signaling and may provide a target for the development of novel therapeutic modalities in immunologically mediated diseases.