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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4179590
- author
- Sun, Jianmin
LU
; Mohlin, Sofie
LU
; Lundby, A
; Kazi, Julhash U.
LU
; Hellman, U
; Påhlman, Sven
LU
; Olsen, J V
and Rönnstrand, Lars
LU
- organization
- publishing date
- 2014
- 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
- pmid:24213578
- scopus:85027922661
- ISSN
- 1476-5594
- DOI
- 10.1038/onc.2013.479
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200), Experimental Clinical Chemistry (013016010)
- 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
- 2016-04-01 10:35:26
- date last changed
- 2025-04-04 14:58:20
@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 = {{https://lup.lub.lu.se/search/files/1970964/4392756.pdf}},
doi = {{10.1038/onc.2013.479}},
volume = {{33}},
year = {{2014}},
}