Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT
Copyright policy )Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT
Abstract Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.
- University of California, San Diego United States
- University of California, San Diego United States
- Indiana University United States
- Queen's University Canada
- Emory University United States
Mice, Inbred C3H, Myeloproliferative Disorders, Integrases, Blotting, Western, Apoptosis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Hematopoietic Stem Cells, Class Ia Phosphatidylinositol 3-Kinase, Mice, Inbred C57BL, Mice, Proto-Oncogene Proteins c-kit, Cell Transformation, Neoplastic, Mutation, Animals, Humans, Immunoprecipitation, Phosphorylation, Bone Marrow Transplantation, Cell Proliferation, GRB2 Adaptor Protein
Mice, Inbred C3H, Myeloproliferative Disorders, Integrases, Blotting, Western, Apoptosis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Hematopoietic Stem Cells, Class Ia Phosphatidylinositol 3-Kinase, Mice, Inbred C57BL, Mice, Proto-Oncogene Proteins c-kit, Cell Transformation, Neoplastic, Mutation, Animals, Humans, Immunoprecipitation, Phosphorylation, Bone Marrow Transplantation, Cell Proliferation, GRB2 Adaptor Protein
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