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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.
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