Critical role for Kit-mediated Src kinase but not PI 3-kinase signaling in pro T and pro B cell development.
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.
Agosti
Valter
V
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Corbacioglu
Selim
S
Ehlers
Imke
I
Waskow
Claudia
C
Sommer
Gunhild
G
Berrozpe
Georgina
G
Kissel
Holger
H
Tucker
Christine M
CM
Manova
Katia
K
Moore
Malcolm A S
MA
Rodewald
Hans-Reimer
HR
Besmer
Peter
P
D000367:Age Factors; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D015153:Blotting, Western; D017931:DNA Primers; D005434:Flow Cytometry; D006652:Histological Techniques; D000068877:Imatinib Mesylate; D038041:Lymphopoiesis / Q000187:drug effects / Q000235:genetics; D008297:Male; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013091:Spermatogenesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000033:anatomy & histology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D017931:DNA Primers; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D019061:src-Family Kinases