REQUIREMENT FOR AN INITIAL SIGNAL FROM THE MEMBRANE-PROXIMAL REGION OF THE INTERLEUKIN-2 RECEPTOR GAMMA(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-2 R beta and gamma(c), which associate with the tyrosine kinases Jak1 an d Jak3, respectively, Genetic and molecular studies have demonstrated that Jak3 is essential for mitogenic signaling by the gamma(c) chain; because it is also the only molecule known to associate with gamma(c), we speculated that Jak3 might be sufficient for signaling by this cha in, Therefore, fusion proteins were constructed in which all or part o f the cytoplasmic domain of gamma(c) was replaced by Jak3. Signaling w as evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric I L-2R beta and gamma(c) chains that bind and are activated by the cytok ine granulocyte-macrophage colony-stimulating factor, Chimeric gamma(c ) chains containing only Jak3 in the cytoplasmic domain failed to medi ate proliferation of CTLL-2 cells, but addition of a conserved membran e-proximal (PROX) domain of gamma(c) in tandem with Jak3 fully reconst ituted gamma(c) function, The requirement for the PROX domain reflecte d an essential role in the activation of Jak3 in vivo, Despite lacking defined catalytic motifs, PROX induced an early Jak-independent signa l, including tyrosine phosphorylation of IL-2R beta and the tyrosine p hosphatase SHP-2. The results define the minimal signaling components of gamma(c) and suggest a new mechanism by which the IL-2R initiates s ignaling in response to ligand.