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

Sun, Jianmin LU ; Mohlin, Sofie LU ; Lundby, A; Kazi, Julhash U. LU ; Hellman, U; Påhlman, Sven LU ; Olsen, J V and Rönnstrand, Lars LU (2014) In Oncogene 33(46). p.5360-5369
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... (More)
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.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.479. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncogene
volume
33
issue
46
pages
5360 - 5369
publisher
Nature Publishing Group
external identifiers
  • pmid:24213578
  • wos:000345120600006
  • scopus:84922563857
ISSN
1476-5594
DOI
10.1038/onc.2013.479
language
English
LU publication?
yes
id
48002dc6-ba59-4aa6-98a7-a7d6ebe71301 (old id 4179590)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24213578?dopt=Abstract
date added to LUP
2013-12-04 14:20:41
date last changed
2017-02-19 14:35:44
@article{48002dc6-ba59-4aa6-98a7-a7d6ebe71301,
  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.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.479.},
  author       = {Sun, Jianmin and Mohlin, Sofie and Lundby, A and Kazi, Julhash U. and Hellman, U and Påhlman, Sven and Olsen, J V and Rönnstrand, Lars},
  issn         = {1476-5594},
  language     = {eng},
  number       = {46},
  pages        = {5360--5369},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner.},
  url          = {http://dx.doi.org/10.1038/onc.2013.479},
  volume       = {33},
  year         = {2014},
}