KIT regulates tyrosine phosphorylation and nuclear localization of β-catenin in mast cell leukemia

Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector β-catenin and deregulated β-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for β-catenin in mast cell leukemia has not been described. Nuclear accumulation of β-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and β-catenin signaling in mast cell leukemia. β-Catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. β-Catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of β-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and β-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of β-catenin directly. Aberrant β-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.