Open AccessRequirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor γ c chain for Janus kinase activation leading to T cell proliferation
Author(s) -
Brad H. Nelson,
Bryan C. McIntosh,
Lori L. Rosencrans,
Philip D. Greenberg
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.5.1878
Subject(s) - microbiology and biotechnology , signal transduction , tyrosine phosphorylation , janus kinase , phosphorylation , biology , tyrosine kinase , janus kinase 1 , receptor tyrosine kinase , chemistry
The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2Rβ and γc , which associate with the tyrosine kinases Jak1 and Jak3, respectively. Genetic and molecular studies have demonstrated that Jak3 is essential for mitogenic signaling by the γc chain; because it is also the only molecule known to associate with γc , we speculated that Jak3 might be sufficient for signaling by this chain. Therefore, fusion proteins were constructed in which all or part of the cytoplasmic domain of γc was replaced by Jak3. Signaling was evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric IL-2Rβ and γc chains that bind and are activated by the cytokine granulocyte–macrophage colony-stimulating factor. Chimeric γc chains containing only Jak3 in the cytoplasmic domain failed to mediate proliferation of CTLL-2 cells, but addition of a conserved membrane-proximal (PROX) domain of γc in tandem with Jak3 fully reconstituted γc function. The requirement for the PROX domain reflected an essential role in the activation of Jak3in vivo . Despite lacking defined catalytic motifs, PROX induced an early Jak-independent signal, including tyrosine phosphorylation of IL-2Rβ and the tyrosine phosphatase SHP-2. The results define the minimal signaling components of γc and suggest a new mechanism by which the IL-2R initiates signaling in response to ligand.