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 (Kit(Y719)) or Src kinase (Kit(Y567)) have been mutated. Whereas steady-state hematopoiesis is normal in Kit(Y719F/Y719F) and Kit(Y567F/Y567F) mice, lymphopoiesis is affected differentially. The Kit(Y567F) mutation, but not the Kit(Y719F) 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 Kit(Y567F/Y567F) and Kit(W/W) mice. The two mutations do not affect embryonic gametogenesis but the Kit(Y719F) mutation blocks spermatogenesis at the spermatogonial stages and in contrast the Kit(Y567F) 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.