Abstract
Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1-/- mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Proliferation / drug effects*
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / metabolism
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Immunoprecipitation
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Mice
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Mice, Knockout
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Mutation / genetics*
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Phosphorylation
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Protein Kinases / physiology*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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RNA, Messenger
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Granulocyte-Macrophage Colony-Stimulating Factor
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Protein Kinases
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KSR-1 protein kinase
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse