Oncogenic mutants of c-Kit are often found in mastocytosis, gastrointestinal stromal tumors and acute myeloid leukemia. The activation mechanism of the most commonly occurring mutation, D816V in exon 17 of c-Kit, has been well-studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant. Phosphorylation of downstream signaling proteins induced by the ligand for c-Kit, stem cell factor, was stronger in c-Kit/V560D expressing cells than in cells expressing c-kit/D816V. Although cells expressing c-Kit/V560D showed increased ligand-independent proliferation and survival compared to wild-type c-Kit-expressing cells, these biological effects were weaker than in c-Kit/D816V-expressing cells. In contrast to cells expressing wild-type c-Kit, cells expressing c-Kit/V560D were independent of Src family kinases for downstream signaling. However, the independence of Src family kinases was not due to a Src-like kinase activity that c-Kit/D816V displayed. Point mutations that selectively block the association of PI3 kinase with c-Kit/V560D inhibited ligand-independent activation of the receptor, while inhibition of the kinase activity of PI3 kinase with pharmacological inhibitors did not affect the kinase activity of the receptor. This suggests a lipid kinase-independent key role of PI3 kinase in c-Kit/V560D-mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive therapeutic target in malignancies induced by c-Kit mutations independent of its lipid kinase activity.
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This research was supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Strategic Cancer Research Program at Lund University, BioCARE, ALF governmental clinical grant, Stiftelsen Olle Engkvist Byggmästare, Alfred Österlund Foundation, Gunnar Nilsson Cancer Society, Kungliga Fysiografiska Sällskapet i Lund, Ollie and Elof Ericssons Stiftelse, Åke-Wiberg Stiftelse, Lars Hiertas Minne Stiftelse, Harald Jeanssons Stiftelse and Harald och Greta Jeanssons Stiftelse, Swedish Childhood Cancer Foundation, MAS Cancer Foundation and SUS Hospital Funds.
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The authors declare that they have no conflicts of interest.
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Lindblad, O., Kazi, J.U., Rönnstrand, L. et al. PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner. Cell. Mol. Life Sci. 72, 4399–4407 (2015). https://doi.org/10.1007/s00018-015-1944-9
- Receptor tyrosine kinase