Requirement 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

The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2Rβ and γ c, which associate with the tyrosine kinases Jak1 and Jak3, respectively. Genetic and molecular studies have demonstrated that Jak3 is essential for mi...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-03, Vol.94 (5), p.1878-1883
Main Authors: Nelson, Brad H., McIntosh, Bryan C., Rosencrans, Lori L., Greenberg, Philip D.
Format: Article
Language:English
Subjects:
Antibodies
Biological Sciences
Catalytic activity
Immunoprecipitation
Ligands
Mice
Molecular chains
Molecules
Phosphorylation
Receptors
T lymphocytes
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Summary:The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2Rβ and γ c, 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 γ c chain; because it is also the only molecule known to associate with γ c, 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 γ c was replaced by Jak3. Signaling was evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric IL-2Rβ and γ c chains that bind and are activated by the cytokine granulocyte-macrophage colony-stimulating factor. Chimeric γ c chains containing only Jak3 in the cytoplasmic domain failed to mediate proliferation of CTLL-2 cells, but addition of a conserved membraneproximal (PROX) domain of γ c in tandem with Jak3 fully reconstituted γ c function. The requirement for the PROX domain reflected an essential role in the activation of Jak3 in 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 γ c and suggest a new mechanism by which the IL-2R initiates signaling in response to ligand.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.5.1878