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| Subject Categories: Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 1456–1466, doi:10.1038/sj.emboj.7601485 Published online 22 February 2007 |
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Bcr-Abl stabilizes  -catenin in chronic myeloid leukemia through its tyrosine phosphorylation |
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| Addolorata Maria Luce Coluccia1, 2, Angelo Vacca2, Mireia Duñach3, Luca Mologni1, Sara Redaelli1, Victor H Bustos4, Daniela Benati1, Lorenzo A Pinna4, 5 and Carlo Gambacorti-Passerini1, 6 |
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1 Department of Clinical Medicine, University of Milano-Bicocca, Monza, Italy 2 Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy 3 Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, Spain 4 Venetian Institute for Molecular Medicine (VIMM), Padova, Italy 5 Department of Biological Chemistry, University of Padova, Padova, Italy 6 Department of Oncology/JGH, McGill University, Montreal, Quebec, Canada To whom correspondence should be addressed Addolorata Maria Luce Coluccia, Department of Clinical Medicine, University of Milano-Bicocca, via Cadore 48, 20052 Monza, Milan, Italy. Tel.: +39 02 64488059; Fax: +39 02 64488363; E-mail: g_lagna@hotmail.com Received 4 April 2006; Accepted 7 November 2006; Published online 22 February 2007. |
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| Abstract |
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| Self-renewal of Bcr-Abl+ chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated -catenin. Although -catenin can be tyrosine (Y)-phosphorylated, the occurrence and biological relevance of this covalent modification in Bcr-Abl-associated leukemogenesis is unknown. Here we show that Bcr-Abl levels control the degree of -catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with -catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate -catenin at Y86 and Y654 residues. This Y-phospho -catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the -catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated -catenin, which presents an increased binding affinity for the Axin/GSK3 complex. Although Bcr-Abl does not affect GSK3 autophosphorylation, it prevents, through its effect on -catenin Y phosphorylation, Axin/GSK3 binding to -catenin and its subsequent S/T phosphorylation. Silencing of -catenin by small interfering RNA inhibited proliferation and clonogenicity of Bcr-Abl+ CML cells, in synergism with Imatinib. These findings indicate the Bcr-Abl triggered Y phosphorylation of -catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML. |
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| Keywords: Bcr-Abl, -catenin protein stability, CML |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHA GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins Nature Immunology Article (01 Jun 2001) Allosteric inhibitors of Bcr-abl?dependent cell proliferation Nature Chemical Biology Article (01 Feb 2006) Leukemia Original Article |
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