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Related Collections Hematopoiesis and Stem Cells Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2001, Vol. 98, No. 5, pp. 1365-1373 HEMATOPOIESIS Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant RuJu Chian, Sonia Young, Alla Danilkovitch-Miagkova, Lars Rönnstrand, Edward Leonard, Petranel Ferrao, Leonie Ashman, and Diana Linnekin From the Basic Research Laboratory and the Laboratory of Immunobiology, Division of Basic Sciences, National Cancer Institute-Frederick, MD; the Hanson Center for Cancer Research, Institute of Medical and Veterinary Science and the Department of Medicine, University of Adelaide, Australia; and the Ludwig Institute for Cancer Research, Biomedicum, Uppsala, Sweden. Stem cell factor (SCF) binds the receptor tyrosine kinase c-Kit and is critical for normal hematopoiesis. Substitution of valine for aspartic acid 816 (D816V) constitutively actives human c-Kit, and this mutation is found in patients with mastocytosis, leukemia, and germ cell tumors. Immortalized murine progenitor cells (MIHCs) transduced with wild-type c-Kit proliferate in response to SCF, whereas cells expressing D816V c-Kit (MIHC-D816V) are factor-independent and tumorigenic. However, the mechanisms mediating transformation by D816V c-Kit are unknown. The objective of this study was to identify signaling components that contribute to D816V c-Kit-mediated transformation. SCF stimulates association of p85PI3K with phosphorylated tyrosine 721 of wild-type c-Kit. Phosphatidylinositol 3 kinase (PI3K) subsequently contributes to the activation of Akt and Jnks. In contrast, these studies demonstrated that the D816V c-Kit mutant was constitutively associated with phosphorylated p85PI3K, and, downstream of PI3K, Jnk 1 and Jnk 2 were activated but Akt was not. Interestingly, Erks 1 and 2 were not constitutively activated by D816V c-Kit. Thus, D816V c-Kit maintains the activity of PI3K but not of all signaling pathways activated by wild-type c-Kit. Further, all pathways downstream of PI3K are not constitutively active in MIHC-D816V cells. Studies with a PI3K inhibitor and D816V/Y721F c-Kit, a mutant incapable of recruiting PI3K, indicate that constitutive activation of PI3K through direct recruitment by D816V c-Kit plays a role in factor-independent growth of MIHC and is critical for tumorigenicity. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Bougherara, F. Subra, R. Crepin, P. Tauc, C. Auclair, and M.-A. Poul The Aberrant Localization of Oncogenic Kit Tyrosine Kinase Receptor Mutants Is Reversed on Specific Inhibitory Treatment Mol. Cancer Res., September 1, 2009; 7(9): 1525 - 1533. 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