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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1840-1847.
Prepublished online as a Blood First Edition Paper on June 6, 2007; DOI 10.1182/blood-2005-12-028019.
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HEMATOPOIESIS
Direct interaction between Kit and the interleukin-7 receptor
Thomas Jahn1,
Simran Sindhu1,
Stacie Gooch1,
Petra Seipel1,
Philip Lavori2,
Erica Leifheit1, and
Kenneth Weinberg1
1 Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles;
2 Department of Health Research and Policy–Biostatistics, Stanford School of Medicine, CA
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 nonhematopoietic 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 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.
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[Abstract]
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