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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.

Author information

1
Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
2
Center for Molecular Pathology, Department of Laboratory Medicine, CREATE Health, Lund University, Skåne University Hospital, Malmö, Sweden.
3
Novo Nordisk Foundation Center for Protein Research, Department of Proteomics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Ludwig Institute for Cancer Research, Uppsala, Sweden.

Abstract

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.

PMID:
24213578
DOI:
10.1038/onc.2013.479
[Indexed for MEDLINE]

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