Self-renewal of Bcr-Abl+ chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated β-catenin. Although β-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 β-catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with β-catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate β-catenin at Y86 and Y654 residues. This Y-phospho β-catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the β-catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated β-catenin, which presents an increased binding affinity for the Axin/GSK3β complex. Although Bcr-Abl does not affect GSK3β autophosphorylation, it prevents, through its effect on β-catenin Y phosphorylation, Axin/GSK3β binding to β-catenin and its subsequent S/T phosphorylation. Silencing of β-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 β-catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML.

Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation / Coluccia, Addolorata Maria Luce; Vacca, Angelo; Dũach, Mireia; Mologni, Luca; Redaelli, Sara; Bustos, Victor H.; Benati, Daniela; Pinna, Lorenzo A.; Gambacorti-Passerini, Carlo. - In: EMBO JOURNAL. - ISSN 0261-4189. - 26:5(2007), pp. 1456-1466. [10.1038/sj.emboj.7601485]

Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation

Benati, Daniela;
2007

Abstract

Self-renewal of Bcr-Abl+ chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated β-catenin. Although β-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 β-catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with β-catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate β-catenin at Y86 and Y654 residues. This Y-phospho β-catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the β-catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated β-catenin, which presents an increased binding affinity for the Axin/GSK3β complex. Although Bcr-Abl does not affect GSK3β autophosphorylation, it prevents, through its effect on β-catenin Y phosphorylation, Axin/GSK3β binding to β-catenin and its subsequent S/T phosphorylation. Silencing of β-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 β-catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML.
2007
26
5
1456
1466
Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation / Coluccia, Addolorata Maria Luce; Vacca, Angelo; Dũach, Mireia; Mologni, Luca; Redaelli, Sara; Bustos, Victor H.; Benati, Daniela; Pinna, Lorenzo A.; Gambacorti-Passerini, Carlo. - In: EMBO JOURNAL. - ISSN 0261-4189. - 26:5(2007), pp. 1456-1466. [10.1038/sj.emboj.7601485]
Coluccia, Addolorata Maria Luce; Vacca, Angelo; Dũach, Mireia; Mologni, Luca; Redaelli, Sara; Bustos, Victor H.; Benati, Daniela; Pinna, Lorenzo A.; Gambacorti-Passerini, Carlo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1153620
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