The PI3-kinase isoform p110 delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner
2014 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 33, no 46, 5360-5369 p.Article in journal (Refereed) Published
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 p110 delta 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 p110 delta has a lipid-kinaseindependent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110 delta is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110 delta 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 p110 delta in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110 delta could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.
Place, publisher, year, edition, pages
2014. Vol. 33, no 46, 5360-5369 p.
c-Kit, c-Kit/D816V, PI3-kinase, p110 delta, phosphorylation, cell transformation
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-239984DOI: 10.1038/onc.2013.479ISI: 000345120600006PubMedID: 24213578OAI: oai:DiVA.org:uu-239984DiVA: diva2:775919