Interaction of IL-2R$\beta$ and $\gamma_c$ Chains with Jak1 and Jak3: Implications for XSCID and XCID

• Published in: Science (American Association for the Advancement of Science) 1994-11, Vol.266 (5187), p.1042-1045
• Main Authors: Russell, Sarah M., Johnston, James A., Noguchi, Masayuki, Kawamura, Masaru, Bacon, Chris M., Friedmann, Michael, Berg, Maria, McVicar, Daniel W., Witthuhn, Bruce A., Silvennoinen, Olli, Goldman, Armond S., Schmalstieg, Frank C., Ihle, James N., O'Shea, John J., Leonard, Warren J.
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Antibodies; Antiserum; Biological and medical sciences; Cell Line; COS cells; Cytokines; Dimerization; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Interleukin-2 - pharmacology; Janus Kinase 1; Janus Kinase 3; Lymphokines, interleukins ( function, expression); Mutation; Phosphorylation; Physiological immunosuppression; Point Mutation; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptors; Receptors, Interleukin-2 - genetics; Receptors, Interleukin-2 - metabolism; Regulatory factors and their cellular receptors; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; Severe Combined Immunodeficiency - metabolism; T lymphocytes; Transfection; Truncation; Tyrosine - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.7973658

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor $\beta$ (IL-2R$\beta$) and common $\gamma$ ($\gamma_c$) chains. Mutations of $\gamma_c$ can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain $\gamma_c$), and IL-9 (whose receptor is shown here to contain $\gamma_c$) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R$\beta$ and $\gamma_c$, respectively; IL-2 induced Jak3-IL-2R$\beta$ and increased Jak3-$\gamma_c$ associations. Truncations of $\gamma_c$, and a $\gamma_c$, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased $\gamma_c$-Jak3 association. Thus, $\gamma_c$ mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.