The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals.
JAK3 is a protein tyrosine kinase that specifically associates with the common gamma chain (gammac), a shared subunit of receptors for interleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or gammac presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3-gammac interaction. Despite the key roles of JAK3 and gammac 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 gammac association. By developing a number of chimeric JAK3-JAK2 constructs, we show that the binding specificity to gammac can be conferred to JAK2 by transferring the N-terminal domains of JAK3. Moreover, those JAK3-JAK2 chimeras capable of binding gammac were also capable of reconstituting IL-2 signaling as measured by inducible phosphorylation of the chimeric JAK3-JAK2 protein, JAK1, the IL-2 receptor beta 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 gammac association. Furthermore, expression of the mutant containing only the JH7-6 domains effectively competed with full-length JAK3 for binding to gammac. We conclude that the JH7-6 domains of JAK3 are necessary and sufficient for gammac 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.
Chen
M
M
Lymphocyte Cell Biology Section, Arthritis-Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cheng
A
A
Chen
Y Q
YQ
Hymel
A
A
Hanson
E P
EP
Kimmel
L
L
Minami
Y
Y
Taniguchi
T
T
Changelian
P S
PS
O'Shea
J J
JJ
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D007142:Immunoglobulin gamma-Chains / Q000737:chemistry* / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D053616:Janus Kinase 3; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D007142:Immunoglobulin gamma-Chains; D007376:Interleukin-2; D018123:Receptors, Interleukin; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3