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

Research output: Contribution to journalArticle

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.

Details

Authors
  • D Arora
  • D Stopp
  • SA Böhmer
  • J Schons
  • R Godfrey
  • Kristina Masson
  • Elena Razumovskaya
  • Lars Rönnstrand
  • S Tanzer
  • R Bauer
  • Frank D. Böhmer
  • JP Muller
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)10918-10929
JournalJournal of Biological Chemistry
Volume286
Issue number13
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)

Related research output

Elena Razumovskaya, 2011, Department of Laboratory Medicine, Lund University. 138 p.

Research output: ThesisDoctoral Thesis (compilation)

View all (1)