Direct interaction between Kit and the interleukin-7 receptor.
In vivo analyses of thymopoiesis in mice defective in signaling through Kit and gammac or Kit and IL-7Ralpha demonstrate synergy and partial complementation of gammac 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 gammac and IL-7Ralpha in the absence of IL-7. Activated Kit formed a complex with either IL-7Ralpha or gammac, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that gammac and IL-7Ralpha 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 gammac-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.
Jahn
Thomas
T
Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, CA, USA. tjahn@stanford.edu
Sindhu
Simran
S
Gooch
Stacie
S
Seipel
Petra
P
Lavori
Philip
P
Leifheit
Erica
E
Weinberg
Kenneth
K
D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology*; D015851:Interleukin-7; D053616:Janus Kinase 3 / Q000378:metabolism; D019169:Jurkat Cells / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor; D015534:Trans-Activators; D014443:Tyrosine / Q000378:metabolism
D053631:Interleukin Receptor Common gamma Subunit; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; C415350:interleukin-7 receptor, alpha chain; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit; D053616:Janus Kinase 3