Advanced

Oncogenic flt3 receptors display different specificity and kinetics of autophosphorylation.

Razumovskaya, Elena LU ; Masson, Kristina LU ; Khan, Rasheed LU ; Bengtsson, Susanne LU and Rönnstrand, Lars LU (2009) In Experimental Hematology 37. p.979-989
Abstract
OBJECTIVE: Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants. METHODS: We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the... (More)
OBJECTIVE: Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants. METHODS: We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the use of a panel of phospho-specific antibodies directed against potential tyrosine phosphorylation sites in FLT3, we identified several novel phosphorylation sites in FLT3 and studied the kinetics and specificity of ligand-induced phosphorylation in living cells. RESULTS: Eight phosphorylated tyrosines (pY589, pY591, pY599, pY726, pY768, pY793, pY842 and pY955) were investigated and shown to be differentially phosphorylated in the wild-type versus the mutated receptors. Furthermore, we show that tyrosines 726, 793 and 842 are novel phosphorylation sites of FLT3 in intact cells. CONCLUSION: In this study, we have looked at the site-specific phosphorylation in the wild-type FLT3 in comparison to the mutants found in AML. We observed not only quantitative changes but more importantly, qualitative differences in the phosphorylation patterns of the wild-type and the mutated FLT3 receptors, which might enhance the understanding of the mechanisms by which FLT3 contributes to AML in patients with mutations in FLT3. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
37
pages
979 - 989
publisher
Elsevier
external identifiers
  • wos:000268373400011
  • pmid:19477218
  • scopus:67650079715
ISSN
1873-2399
DOI
10.1016/j.exphem.2009.05.008
language
English
LU publication?
yes
id
ee4862cb-5b55-4779-a062-870db5b2ed07 (old id 1411924)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19477218?dopt=Abstract
date added to LUP
2009-06-03 14:24:31
date last changed
2017-11-05 04:44:53
@article{ee4862cb-5b55-4779-a062-870db5b2ed07,
  abstract     = {OBJECTIVE: Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants. METHODS: We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the use of a panel of phospho-specific antibodies directed against potential tyrosine phosphorylation sites in FLT3, we identified several novel phosphorylation sites in FLT3 and studied the kinetics and specificity of ligand-induced phosphorylation in living cells. RESULTS: Eight phosphorylated tyrosines (pY589, pY591, pY599, pY726, pY768, pY793, pY842 and pY955) were investigated and shown to be differentially phosphorylated in the wild-type versus the mutated receptors. Furthermore, we show that tyrosines 726, 793 and 842 are novel phosphorylation sites of FLT3 in intact cells. CONCLUSION: In this study, we have looked at the site-specific phosphorylation in the wild-type FLT3 in comparison to the mutants found in AML. We observed not only quantitative changes but more importantly, qualitative differences in the phosphorylation patterns of the wild-type and the mutated FLT3 receptors, which might enhance the understanding of the mechanisms by which FLT3 contributes to AML in patients with mutations in FLT3.},
  author       = {Razumovskaya, Elena and Masson, Kristina and Khan, Rasheed and Bengtsson, Susanne and Rönnstrand, Lars},
  issn         = {1873-2399},
  language     = {eng},
  pages        = {979--989},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Oncogenic flt3 receptors display different specificity and kinetics of autophosphorylation.},
  url          = {http://dx.doi.org/10.1016/j.exphem.2009.05.008},
  volume       = {37},
  year         = {2009},
}