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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Bone Marrow Transplantation
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology*
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Class Ia Phosphatidylinositol 3-Kinase / metabolism
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GRB2 Adaptor Protein / physiology*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Immunoprecipitation
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Integrases / metabolism
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mutation / genetics*
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Myeloproliferative Disorders / etiology*
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Myeloproliferative Disorders / mortality
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Myeloproliferative Disorders / prevention & control*
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Phosphorylation / drug effects
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology*
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Proto-Oncogene Proteins c-kit / genetics*
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Proto-Oncogene Proteins c-kit / metabolism
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Signal Transduction / drug effects
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Survival Rate
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Tyrosine / metabolism
Substances
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GRB2 Adaptor Protein
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Grb2 protein, mouse
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Tyrosine
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Class Ia Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-kit
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Cre recombinase
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Integrases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11