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

Abstract

Deregulated accumulation of nuclear beta-catenin enhances transcription of beta-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 beta-catenin-dependent nuclear signaling. Tyrosine phosphorylation of beta-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and beta-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 beta-catenin. Although beta-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 beta-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of beta-catenin. Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.

• Authors: T Kajiguchi, E J Chung, S Lee, A Stine, H Kiyoi, T Naoe, M J Levis, L Neckers, J B Trepel
• Journal: Leukemia (Leukemia) Vol. 21 Issue 12 Pg. 2476-84 (Dec 2007) ISSN: 1476-5551 [Electronic] England
• PMID: 17851558 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-3
• Membrane Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Recombinant Proteins
• Tyrphostins
• beta Catenin
• flt3 ligand protein
• 6,7-dimethoxy-3-phenylquinoxaline
• Phosphotyrosine
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• Staurosporine
• midostaurin

Topics

• Active Transport, Cell Nucleus (physiology)
• Acute Disease
• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Leukemic
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, physiology)
• Glycogen Synthase Kinase 3 beta
• Humans
• Interleukin-3 (pharmacology)
• Leukemia, Myeloid (genetics, metabolism, pathology)
• Membrane Proteins (pharmacology)
• Mice
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Phosphorylation
• Phosphotyrosine (metabolism)
• Protein Processing, Post-Translational (physiology)
• RNA, Small Interfering (pharmacology)
• Recombinant Proteins (metabolism)
• Staurosporine (analogs & derivatives, pharmacology)
• Transcription, Genetic (physiology)
• Tyrphostins (pharmacology)
• beta Catenin (genetics, metabolism)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics, physiology)