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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1542-1550. Prepublished online as a Blood First Edition Paper on May 9, 2006; DOI 10.1182/blood-2005-07-008896. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2005-07-008896v1 108/5/1542    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 Heiss, E. Articles by Rönnstrand, L. Search for Related Content PubMed PubMed Citation Articles by Heiss, E. Articles by Rönnstrand, L. Related Collections Hematopoiesis and Stem Cells Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2 Elke Heiss, Kristina Masson, Christina Sundberg, Malin Pedersen, Jianmin Sun, Susanne Bengtsson, and Lars Rönnstrand From Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden. Early signal relay steps upon ligand binding to the receptor tyrosine kinase Flt3 (ie, sites of Flt3 autophosphorylation and subsequent docking partners) are mainly unresolved. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region of human Flt3 and subsequent radiosequencing, we identified the tyrosine residues 572, 589, 591, and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we examined Flt3 ligand (FL)-mediated responses in wild-type-Flt3-(WT-Flt3-), Y589F-Flt3-, and Y599F-Flt3-expressing 32D cells. Compared with WT-Flt3-32D cells upon ligand stimulation, 32D-Y589F-Flt3 showed enhanced Erk activation and proliferation/survival, whereas 32D-Y599F-Flt3 cells hereby displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for signal relay molecules including Src family kinases and SHP2. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed decreased FL-triggered activation of Src family kinases. Interference with the Src-dependent negative regulation of Flt3 signaling may account for the enhanced mitogenic response of Y589F-Flt3. Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Reindl, H. Quentmeier, K. Petropoulos, P. A. Greif, T. Benthaus, B. Argiropoulos, G. Mellert, S. Vempati, J. Duyster, C. Buske, et al. CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome Subtypes Clin. Cancer Res., April 1, 2009; 15(7): 2238 - 2247. [Abstract] [Full Text] [PDF] A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Blood, March 5, 2009; 113(10): 2302 - 2311. [Abstract] [Full Text] [PDF] S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591 Clin. Cancer Res., July 15, 2008; 14(14): 4437 - 4445. [Abstract] [Full Text] [PDF] C. Choudhary, C. Brandts, J. Schwable, L. Tickenbrock, B. Sargin, A. Ueker, F.-D. Bohmer, W. E. Berdel, C. Muller-Tidow, and H. Serve Activation mechanisms of STAT5 by oncogenic Flt3-ITD Blood, July 1, 2007; 110(1): 370 - 374. [Abstract] [Full Text] [PDF] J. M. Irish, N. Anensen, R. Hovland, J. Skavland, A.-L. Borresen-Dale, O. Bruserud, G. P. Nolan, and B. T. Gjertsen Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53 Blood, March 15, 2007; 109(6): 2589 - 2596. [Abstract] [Full Text] [PDF]

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