The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published 15 March 2004. doi:10.1084/jem.20031983
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 867-878
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Critical Role for Kit-mediated Src Kinase But Not PI 3-Kinase Signaling in Pro T and Pro B Cell Development

Valter Agosti1, Selim Corbacioglu1, Imke Ehlers1, Claudia Waskow4, Gunhild Sommer1, Georgina Berrozpe1, Holger Kissel1, Christine M. Tucker1, Katia Manova1, Malcolm A.S. Moore2,3, Hans-Reimer Rodewald4, and Peter Besmer1,3

1 Developmental Biology and 2 Cell Biology Programs, Sloan-Kettering Institute, 3 Cornell University Graduate School of Medical Sciences, New York, NY 10021
4 Department for Immunology, University of Ulm, D-89070 Ulm, Germany

Address correspondence to Peter Besmer, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-8188; Fax: (646) 422-2355; email: p-besmer{at}ski.mskcc.org

The Kit receptor functions in hematopoiesis, lymphocyte development, gastrointestinal tract motility, melanogenesis, and gametogenesis. To investigate the roles of different Kit signaling pathways in vivo, we have generated knock-in mice in which docking sites for PI 3-kinase (KitY719) or Src kinase (KitY567) have been mutated. Whereas steady-state hematopoiesis is normal in KitY719F/Y719F and KitY567F/Y567F mice, lymphopoiesis is affected differentially. The KitY567F mutation, but not the KitY719F mutation, blocks pro T cell and pro B cell development in an age-dependent manner. Thus, the Src family kinase, but not the PI 3-kinase docking site in Kit, mediates a critical signal for lymphocyte development. In agreement with these results, treatment of normal mice with the Kit tyrosine kinase inhibitor imatinib (Gleevec®) leads to deficits in pro T and pro B cell development, similar to those seen in KitY567F/Y567F and KitW/W mice. The two mutations do not affect embryonic gametogenesis but the KitY719F mutation blocks spermatogenesis at the spermatogonial stages and in contrast the KitY567F mutation does not affect this process. Therefore, Kit-mediated PI 3-kinase signaling and Src kinase family signaling is highly specific for different cellular contexts in vivo.

Key Words: Kit receptor signaling • Src kinase • PI 3-kinase • pro T and pro B cell development

The online version of this article contains supplemental material.

V. Agosti and S. Corbacioglu contributed equally to this work.

Abbreviations used in this paper: BMMC, BM-derived mast cells; CHK, Csk-homologous kinase; DT-A, diphtheria toxin A; ES, embryonic stem; ICC, interstitial cells of Cajal; KitL, Kit ligand; Sl, Steel; TN, triple negative; W, White spotting.


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