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

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.