Submitted December 29, 2005
Accepted June 1, 2007
Direct interaction between Kit and the interleukin-7 receptor
Thomas Jahn*, Simran Sindhu, Stacie Gooch, Petra Seipel, Philip Lavori, Erica Leifheit, and Kenneth Weinberg
Division of Research Immunology & Bone Marrow Transplantation, Childrens Hospital Los Angeles, Los Angeles, CA
Dept of Health Research and Policy – Biostatistics, Stanford University School of Medicine, Stanford, CA
Division of Stem Cell Transplantation, Dept of Pediatrics, Stanford University School of Medicine, Stanford, CA
* Corresponding author; email: tjahn{at}stanford.edu.
In vivo analyses of thymopoiesis in mice defective in signaling through Kit and 
c or Kit and IL-7R
demonstrate synergy and partial complementation of c or IL-7-mediated signaling by the Kit signaling pathway. Our molecular analysis in T-lymphoid cells as well as in non-hematopoietic cells shows that Kit and IL-7R signaling pathways directly interact. KL-mediated activation of Kit induced strong tyrosine phosphorylation of c and IL-7R in the absence of IL-7. Activated Kit formed a complex with either IL-7R or c, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that c and IL-7R 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 c-containing receptors like 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.
