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KITD816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma

Phung, Bengt LU ; Kazi, Julhash U. LU ; Lundby, Alicia; Bergsteinsdottir, Kristin; Sun, Jianmin LU ; Goding, Colin R; Jonsson, Goran LU ; Olsen, Jesper V; Steingrímsson, Eiríkur and Ronnstrand, Lars LU (2017) In Molecular Cancer Research 15(9). p.1265-1274
Abstract

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cellcycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore... (More)

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cellcycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KITD816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells. Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
melanoma, KITD816V, SRC-Mediated Tyrosine Phosphorylatio, MITF
in
Molecular Cancer Research
volume
15
issue
9
pages
10 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85028806733
  • pmid:28584020
  • wos:000409041400013
ISSN
1541-7786
DOI
10.1158/1541-7786.MCR-17-0149
language
English
LU publication?
yes
id
de27a5e8-d7eb-4153-8759-3ee4adc0fac9
date added to LUP
2017-10-10 10:47:42
date last changed
2018-02-01 09:52:51
@article{de27a5e8-d7eb-4153-8759-3ee4adc0fac9,
  abstract     = {<p>The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD<sup>816V</sup> has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD<sup>816V</sup> induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cellcycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KITD<sup>816V</sup> in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD<sup>816V</sup> transformed cells. Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD<sup>816V</sup>, can alter the transcriptional program of the transcription factor MITF in melanoma.</p>},
  author       = {Phung, Bengt and Kazi, Julhash U. and Lundby, Alicia and Bergsteinsdottir, Kristin and Sun, Jianmin and Goding, Colin R and Jonsson, Goran and Olsen, Jesper V and Steingrímsson, Eiríkur and Ronnstrand, Lars},
  issn         = {1541-7786},
  keyword      = {melanoma,KITD816V,SRC-Mediated Tyrosine Phosphorylatio,MITF},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1265--1274},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Research},
  title        = {KIT<sup>D816V</sup> induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma},
  url          = {http://dx.doi.org/10.1158/1541-7786.MCR-17-0149},
  volume       = {15},
  year         = {2017},
}