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Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

Kazi, Julhash U. LU ; Chougule, Rohit A. LU ; Li, Tianfeng; Su, Xianwei; Moharram, Sausan A. LU ; Rupar, Kaja LU ; Marhäll, Alissa LU ; Mohiuddin, Gazi LU ; Sun, Jianmin LU and Zhao, Hui, et al. (2017) In Cellular and Molecular Life Sciences1997-01-01+01:00 74(14). p.2679-2688
Abstract

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important... (More)

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.

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published
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keywords
Activation loop, Acute myeloid leukemia, FLT3, FLT3-ITD, Microarray, SHP2, Survival, Transformation
in
Cellular and Molecular Life Sciences1997-01-01+01:00
volume
74
issue
14
pages
2679 - 2688
publisher
Birkhaüser
external identifiers
  • scopus:85014561805
  • wos:000403887100012
ISSN
1420-682X
DOI
10.1007/s00018-017-2494-0
language
English
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yes
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85268470-dea1-4ae2-9978-35cd6dbb37e0
date added to LUP
2017-03-14 12:08:07
date last changed
2018-01-07 11:55:16
@article{85268470-dea1-4ae2-9978-35cd6dbb37e0,
  abstract     = {<p>The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.</p>},
  author       = {Kazi, Julhash U. and Chougule, Rohit A. and Li, Tianfeng and Su, Xianwei and Moharram, Sausan A. and Rupar, Kaja and Marhäll, Alissa and Mohiuddin, Gazi and Sun, Jianmin and Zhao, Hui and Rönnstrand, Lars},
  issn         = {1420-682X},
  keyword      = {Activation loop,Acute myeloid leukemia,FLT3,FLT3-ITD,Microarray,SHP2,Survival,Transformation},
  language     = {eng},
  month        = {03},
  number       = {14},
  pages        = {2679--2688},
  publisher    = {Birkhaüser},
  series       = {Cellular and Molecular Life Sciences1997-01-01+01:00},
  title        = {Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD},
  url          = {http://dx.doi.org/10.1007/s00018-017-2494-0},
  volume       = {74},
  year         = {2017},
}