AbstractIn vivo analyses of thymopoiesis in mice defective in signaling through Kit and γc or Kit and IL-7Rα demonstrate synergy and partial complementation of γc or IL-7–mediated signaling by the Kit signaling pathway. Our molecular analysis in T-lymphoid cells as well as in nonhematopoietic cells shows that Kit and IL-7R signaling pathways directly interact. KL-mediated activation of Kit induced strong tyrosine phosphorylation of γc and IL-7Rα in the absence of IL-7. Activated Kit formed a complex with either IL-7Rα or γc, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that γc and IL-7Rα are each direct substrates of Kit. Kit activated Jak3 in an IL-7R–dependent manner. Moreover, deficient Stat5 activation of the Kit mutant YY567/569FF lacking intrinsic Src activation capacity was partially reconstituted in the presence of IL-7R and Jak3. Based on the molecular data, we propose a model of Kit-mediated functional activation of γc-containing receptors such as IL-7R, similar to the interaction between Kit and Epo-R. Such indirect activation of the Jak-Stat pathway induced by the interaction between an RTK and type I cytokine receptor could be the underlying mechanism for a context-specific signaling repertoire of a pleiotropic RTK-like Kit.