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A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.

Masson, Kristina LU ; Liu, Tao LU ; Khan, Rasheed LU ; Sun, Jianmin LU and Rönnstrand, Lars LU (2009) In British Journal of Haematology 146. p.193-202
Abstract
Summary The haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites,... (More)
Summary The haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites, and characterised in terms of proliferation and viability. Interestingly, the Flt3 ITD promoted increased survival but after introducing the triple mutation, this phenotype was lost. When looking into different downstream pathways, this effect was mainly caused by decreased phosphoinositide 3-kinase and Stat5 signalling, and the Flt3 ITD carrying the Grb2 binding mutations showed less Akt and Stat5 activation compared to the regular Flt3 ITD receptor. These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions. (Less)
Please use this url to cite or link to this publication:
author
organization
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type
Contribution to journal
publication status
published
subject
in
British Journal of Haematology
volume
146
pages
193 - 202
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000267657300009
  • pmid:19438505
  • scopus:67650001509
ISSN
0007-1048
DOI
10.1111/j.1365-2141.2009.07725.x
language
English
LU publication?
yes
id
aff40b99-be88-40b2-b6c1-43cc80251977 (old id 1412335)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19438505?dopt=Abstract
date added to LUP
2009-06-03 13:20:38
date last changed
2017-05-21 04:33:18
@article{aff40b99-be88-40b2-b6c1-43cc80251977,
  abstract     = {Summary The haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites, and characterised in terms of proliferation and viability. Interestingly, the Flt3 ITD promoted increased survival but after introducing the triple mutation, this phenotype was lost. When looking into different downstream pathways, this effect was mainly caused by decreased phosphoinositide 3-kinase and Stat5 signalling, and the Flt3 ITD carrying the Grb2 binding mutations showed less Akt and Stat5 activation compared to the regular Flt3 ITD receptor. These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions.},
  author       = {Masson, Kristina and Liu, Tao and Khan, Rasheed and Sun, Jianmin and Rönnstrand, Lars},
  issn         = {0007-1048},
  language     = {eng},
  pages        = {193--202},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {British Journal of Haematology},
  title        = {A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.},
  url          = {http://dx.doi.org/10.1111/j.1365-2141.2009.07725.x},
  volume       = {146},
  year         = {2009},
}