Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality

The mechanism of cell transformation by Fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is incompletely understood. The most prevalent activated mutant FLT3 ITD exhibits an altered signaling quality, including strong activation of the STAT5 transcription factor. FLT3 ITD has also b...

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Bibliographic Details
Published in:	Blood Vol. 113; no. 15; pp. 3568 - 3576
Main Authors:	Schmidt-Arras, Dirk, Böhmer, Sylvia-Annette, Koch, Sina, Müller, Jörg P., Blei, Lutz, Cornils, Hauke, Bauer, Reinhard, Korasikha, Sridhar, Thiede, Christian, Böhmer, Frank-D.
Format:	Journal Article
Language:	English
Published:	Washington, DC Elsevier Inc 09-04-2009 Americain Society of Hematology
Subjects:	Animals Biological and medical sciences Cell Division - physiology Cell Line Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cells, Cultured Endoplasmic Reticulum - metabolism fms-Like Tyrosine Kinase 3 - genetics fms-Like Tyrosine Kinase 3 - metabolism Gene Duplication Hematologic and hematopoietic diseases Humans Kidney - cytology Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Medical sciences Mice Mice, Inbred C3H Mutagenesis Signal Transduction - physiology STAT3 Transcription Factor - metabolism STAT5 Transcription Factor - metabolism Signal transduction Hematology FLT3 gene C-Onc gene Quality trk receptor Endoplasmic reticulum Anchoring Protooncogene
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Summary:	The mechanism of cell transformation by Fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is incompletely understood. The most prevalent activated mutant FLT3 ITD exhibits an altered signaling quality, including strong activation of the STAT5 transcription factor. FLT3 ITD has also been found partially retained as a high-mannose precursor in an intracellular compartment. To analyze the role of intracellular retention of FLT3 for transformation, we have generated FLT3 versions that are anchored in the perinuclear endoplasmic reticulum (ER) by appending an ER retention sequence containing a RRR (R3) motif. ER retention of R3, but not of corresponding A3 FLT3 versions, is shown by biochemical, fluorescence-activated cell sorting, and immunocytochemical analyses. ER anchoring reduced global autophosphorylation and diminished constitutive activation of ERK1/2 and AKT of the constitutively active FLT3 versions. ER anchoring was, however, associated with elevated signaling to STAT3. Transforming activity of the FLT3 D835Y mutant was suppressed by ER anchoring. In contrast, ER-anchored FLT3 ITD retained STAT5-activating capacity and was transforming in vitro and in vivo. The findings highlight another aspect of the different signaling quality of FLT3 ITD: It can transform cells from an intracellular location.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2007-10-121426