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Oncogene. 2014 Nov 13;33(46):5360-9. doi: 10.1038/onc.2013.479. Epub 2013 Nov 11.

The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner.

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Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Center for Molecular Pathology, Department of Laboratory Medicine, CREATE Health, Lund University, Skåne University Hospital, Malmö, Sweden.
Novo Nordisk Foundation Center for Protein Research, Department of Proteomics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Ludwig Institute for Cancer Research, Uppsala, Sweden.


PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110δ in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110δ has a lipid-kinase-independent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110δ is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110δ carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110δ in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110δ could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.

[Indexed for MEDLINE]

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