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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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, J.; Mohlin, S.; Lundby, A.; Kazi, J.U.; Hellman, U.; Påhlman, S.; Olsen, J.V.; Rönnstrand, L.

In: Oncogene, 11.11.2013.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Sun, J, Mohlin, S, Lundby, A, Kazi, JU, Hellman, U, Påhlman, S, Olsen, JV & Rönnstrand, L 2013, 'The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner', Oncogene. https://doi.org/10.1038/onc.2013.479

APA

Sun, J., Mohlin, S., Lundby, A., Kazi, J. U., Hellman, U., Påhlman, S., Olsen, J. V., & Rönnstrand, L. (2013). The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner. Oncogene. https://doi.org/10.1038/onc.2013.479

Vancouver

Sun J, Mohlin S, Lundby A, Kazi JU, Hellman U, Påhlman S et al. The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner. Oncogene. 2013 Nov 11. https://doi.org/10.1038/onc.2013.479

Author

Sun, J. ; Mohlin, S. ; Lundby, A. ; Kazi, J.U. ; Hellman, U. ; Påhlman, S. ; Olsen, J.V. ; Rönnstrand, L. / The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner. In: Oncogene. 2013.

Bibtex

@article{4f0e9f72edbb4687bbffd3ed30ed5e89,
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",
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 = "J. Sun and S. Mohlin and A. Lundby and J.U. Kazi and U. Hellman and S. P{\aa}hlman and J.V. Olsen and L. R{\"o}nnstrand",
year = "2013",
month = nov,
day = "11",
doi = "10.1038/onc.2013.479",
language = "English",
journal = "Oncogene",
issn = "0950-9232",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner

AU - Sun, J.

AU - Mohlin, S.

AU - Lundby, A.

AU - Kazi, J.U.

AU - Hellman, U.

AU - Påhlman, S.

AU - Olsen, J.V.

AU - Rönnstrand, L.

PY - 2013/11/11

Y1 - 2013/11/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887030794&partnerID=8YFLogxK

U2 - 10.1038/onc.2013.479

DO - 10.1038/onc.2013.479

M3 - Journal article

C2 - 24213578

JO - Oncogene

JF - Oncogene

SN - 0950-9232

ER -

ID: 88646431