Critical role for Kit-mediated Src kinase but not PI 3-Kinase signaling in pro T and pro B cell development Journal Article

Authors: Agosti, V.; Corbacioglu, S.; Ehlers, I.; Waskow, C.; Sommer, G.; Berrozpe, G.; Kissel, H.; Tucker, C. M.; Manova, K.; Moore, M. A. S.; Rodewald, H. R.; Besmer, P.
Article Title: Critical role for Kit-mediated Src kinase but not PI 3-Kinase signaling in pro T and pro B cell development
Abstract: 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 (KitY567) have been mutated. Whereas steady-state hematopoiesis is normal in KitY719F/Y719F 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 (GleevecĀ®) leads to deficits in pro T and pro B cell development, similar to those seen in Kit Y567F/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 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.
Keywords: signal transduction; gene mutation; mutation; nonhuman; flow cytometry; polymerase chain reaction; t lymphocyte; t-lymphocytes; animal cell; mouse; animals; mice; imatinib; stem cell factor; proto-oncogene proteins c-kit; cell maturation; age factors; protein tyrosine kinase; pyrimidines; phosphatidylinositol 3 kinase; mice, inbred c57bl; histological techniques; b-lymphocytes; mice, transgenic; lymphocyte differentiation; blotting, western; 1-phosphatidylinositol 3-kinase; mutagenesis, site-directed; piperazines; dna primers; src-family kinases; site directed mutagenesis; lymphopoiesis; testis; pre b lymphocyte; mutagenesis, insertional; b lymphocyte differentiation; spermatogenesis; mast cell; mast cells; src kinase; precipitin tests; male; priority journal; article; kit receptor signaling; pi 3-kinase; pro t and pro b cell development
Journal Title: Journal of Experimental Medicine
Volume: 199
Issue: 6
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2004-03-15
Start Page: 867
End Page: 878
Language: English
DOI: 10.1084/jem.20031983
PROVIDER: scopus
PMCID: PMC2212729
PUBMED: 15024050
Notes: J. Exp. Med. -- Cited By (since 1996):63 -- Export Date: 16 June 2014 -- CODEN: JEMEA -- Source: Scopus
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