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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3568-3576. Prepublished online as a Blood First Edition Paper on February 9, 2009; DOI 10.1182/blood-2007-10-121426. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-10-121426v1 113/15/3568    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schmidt-Arras, D. Articles by Böhmer, F.-D. Search for Related Content PubMed PubMed Citation Articles by Schmidt-Arras, D. Articles by Böhmer, F.-D. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality Dirk Schmidt-Arras1,*, Sylvia-Annette Böhmer1,*, Sina Koch2, Jörg P. Müller1, Lutz Blei1, Hauke Cornils1, Reinhard Bauer1, Sridhar Korasikha1, Christian Thiede2, and Frank-D. Böhmer1 1 Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena; and 2 Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Dresden, Germany 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Bougherara, F. Subra, R. Crepin, P. Tauc, C. Auclair, and M.-A. Poul The Aberrant Localization of Oncogenic Kit Tyrosine Kinase Receptor Mutants Is Reversed on Specific Inhibitory Treatment Mol. Cancer Res., September 1, 2009; 7(9): 1525 - 1533. [Abstract] [Full Text] [PDF]

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