THE AMINO-TERMINUS OF JAK3 IS NECESSARY AND SUFFICIENT FOR BINDING TOTHE COMMON GAMMA-CHAIN AND CONFERS THE ABILITY TO TRANSMIT INTERLEUKIN 2-MEDIATED SIGNALS

JAK3 is a protein tyrosine kinase that specifically associates with th e common gamma chain (gamma(c)), a shared subunit of receptors for int erleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or gamma(c) presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3-gamma (c) interaction. Despite the key roles of JAK3 and gamma(c) in lymphoc ytic development and function, the molecular basis of this Interaction remains poorly understood, In this study, we have characterized the r egions of chimeric involved in gamma(c) association. By developing a n umber of chimeric JAK3-JAK2 constructs, we show that the binding speci ficity to gamma(c) can be conferred to JAK2 by transferring the N-term inal domains of JAK3. Moreover, those JAK3-JAK2 chimeras capable of bi nding gamma(c) were also capable of reconstituting IL-2 signaling as m easured by inducible phosphorylation of the chimeric JAK3-JAK2 protein , JAK1, the IL-2 receptor beta chain, and signal transducer and activa tor of transcription 5A. Subsequent deletion analyses of JAK3 have ide ntified the N-terminal JH7-6 domains as a minimal region sufficient fo r gamma(c) association, Furthermore, expression of the mutant containi ng only tile JH7-6 domains effectively competed with full-length JAK3 for binding to gamma(c). We conclude that the JH7-6 domains of JAK3 ar e necessary and sufficient for gamma(c) association. These studies off er clues toward a broader understanding of JAK-mediated cytokine signa ling and may provide a target for the development of novel therapeutic modalities in immunologically mediated diseases.