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Protein tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling

Arora, D; Stopp, D; Böhmer, SA; Schons, J; Godfrey, R; Masson, Kristina LU ; Razumovskaya, Elena LU ; Rönnstrand, Lars LU ; Tanzer, S and Bauer, R, et al. (2011) In Journal of Biological Chemistry 286(13). p.10918-10929
Abstract
Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia (AML). Little is known about the protein tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable myeloid cell lines with strongly reduced DEP-1... (More)
Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia (AML). Little is known about the protein tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Particularly, the sites pY589, pY591, and pY842 involved in the FLT3 ligand (FL) -mediated activation of FLT3 were hyperphosphorylated most. Enhanced FLT3 phosphorylation in DEP-1 depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Overexpression of DEP-1 resulted in opposite effects on FL-mediated receptor phosphorylation and signaling activity. Furthermore, FL-mediated colony formation in methylcellulose of 32D cells expressing FLT3 was induced in response to shRNA-mediated DEP-1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL-stimulation, but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and its loss may contribute to, but is not sufficient for leukemogenic cell transformation. (Less)
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Journal of Biological Chemistry
volume
286
issue
13
pages
10918 - 10929
publisher
ASBMB
external identifiers
  • wos:000288797100004
  • scopus:79953187287
ISSN
1083-351X
DOI
10.1074/jbc.M110.205021
language
English
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yes
id
ae0e83e1-975e-4932-9817-35a8ce06129a (old id 1784236)
date added to LUP
2011-02-07 13:25:02
date last changed
2017-11-05 03:22:32
@article{ae0e83e1-975e-4932-9817-35a8ce06129a,
  abstract     = {Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia (AML). Little is known about the protein tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Particularly, the sites pY589, pY591, and pY842 involved in the FLT3 ligand (FL) -mediated activation of FLT3 were hyperphosphorylated most. Enhanced FLT3 phosphorylation in DEP-1 depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Overexpression of DEP-1 resulted in opposite effects on FL-mediated receptor phosphorylation and signaling activity. Furthermore, FL-mediated colony formation in methylcellulose of 32D cells expressing FLT3 was induced in response to shRNA-mediated DEP-1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL-stimulation, but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and its loss may contribute to, but is not sufficient for leukemogenic cell transformation.},
  author       = {Arora, D and Stopp, D and Böhmer, SA and Schons, J and Godfrey, R and Masson, Kristina and Razumovskaya, Elena and Rönnstrand, Lars and Tanzer, S and Bauer, R and Böhmer, Frank D. and Muller, JP},
  issn         = {1083-351X},
  language     = {eng},
  number       = {13},
  pages        = {10918--10929},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Protein tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling},
  url          = {http://dx.doi.org/10.1074/jbc.M110.205021},
  volume       = {286},
  year         = {2011},
}