KIT regulates tyrosine phosphorylation and nuclear localization of beta-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 beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-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 beta-catenin signaling in mast cell leukemia. Beta-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. Beta-catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.
Kajiguchi
Tomohiro
T
Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1107, United States.
Lee
Sunmin
S
Lee
Min-Jung
MJ
Trepel
Jane B
JB
Neckers
Len
L
D021581:Active Transport, Cell Nucleus; D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D007946:Leukemia, Mast-Cell / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D001549:Benzamides; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D014443:Tyrosine; D051176:beta Catenin; C495270:CTNNB1 protein, human; C000715470:MAS1 protein, human