FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells

T. Kajiguchi, E. J. Chung, S. Lee, A. Stine, H. Kiyoi, T. Naoe, Mark J Levis, L. Neckers, J. B. Trepel

Research output: Contribution to journalArticle

Abstract

Deregulated accumulation of nuclear β-catenin enhances transcription of β-catenin target genes and promotes malignant transformation. Recently, acute myeloid leukemia (AML) cells with activating mutations of FMS-like tyrosine kinase-3 (FLT3) were reported to display elevated β-catenin-dependent nuclear signaling. Tyrosine phosphorylation of β-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and β-catenin nuclear localization. Compared to cells with wild-type FLT3 (FLT3-WT), cells with the FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) had elevated levels of tyrosine-phosphorylated β-catenin. Although β-catenin was localized mainly in the cytoplasm in FLT3-WT cells, it was primarily nuclear in FLT3-ITD cells. Treatment with FLT3 kinase inhibitors or FLT3 silencing with RNAi decreased β-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of β-catenin. Endogenous β-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant β-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of β-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces β-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and β-catenin oncogeneic signaling in AML.

Original languageEnglish (US)
Pages (from-to)2476-2484
Number of pages9
JournalLeukemia
Volume21
Issue number12
DOIs
StatePublished - Dec 2007

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Catenins
Myeloid Cells
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Tyrosine
Phosphorylation
Mutation

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. / Kajiguchi, T.; Chung, E. J.; Lee, S.; Stine, A.; Kiyoi, H.; Naoe, T.; Levis, Mark J; Neckers, L.; Trepel, J. B.

In: Leukemia, Vol. 21, No. 12, 12.2007, p. 2476-2484.

Research output: Contribution to journalArticle

Kajiguchi, T, Chung, EJ, Lee, S, Stine, A, Kiyoi, H, Naoe, T, Levis, MJ, Neckers, L & Trepel, JB 2007, 'FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells', Leukemia, vol. 21, no. 12, pp. 2476-2484. https://doi.org/10.1038/sj.leu.2404923
Kajiguchi, T. ; Chung, E. J. ; Lee, S. ; Stine, A. ; Kiyoi, H. ; Naoe, T. ; Levis, Mark J ; Neckers, L. ; Trepel, J. B. / FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. In: Leukemia. 2007 ; Vol. 21, No. 12. pp. 2476-2484.
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