Abstract
SHP-2 tyrosine phosphatase is highly expressed in hematopoietic cells, however, the function of SHP-2 in hematopoietic cell signaling is not well understood. Here we focus on the role of SHP-2 phosphatase in the signal transduction of interleukin (IL)-3, a cytokine involved in hematopoietic cell survival, proliferation, and differentiation. We established immortalized SHP-2(-/-) hematopoietic cell pools and showed that IL-3-induced proliferative response was diminished in SHP-2(-/-) cells. Moreover, inhibition of the catalytic activity of SHP-2 in wild-type (WT) bone marrow hematopoietic progenitor cells and Ba/F3 cells by overexpression of catalytically inactive SHP-2 mutant suppressed their differentiative and proliferative responses to IL-3, demonstrating an important positive role for SHP-2 in IL-3 signal transduction. Further biochemical analyses revealed that IL-3-induced Jak/Stat, Erk, and PI3 kinase pathways in SHP-2(-/-) cells were impaired and reintroduction of WT SHP-2 into mutant cells partially restored IL-3 signaling. Interestingly, in catalytically inactive SHP-2-overexpressing Ba/F3 cells, although IL-3-induced activation of Jak2 and Erk kinases was reduced and shortened, PI3 kinase activation remained unaltered. Taken together, these results suggest that SHP-2 tyrosine phosphatase plays multiple roles in IL-3 signal transduction, functioning in both catalytic-dependent and -independent manners in the Jak/Stat, Erk, and PI3 kinase pathways.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Catalysis
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Cell Division / drug effects
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Cell Line, Transformed
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Gene Transfer Techniques
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Homeodomain Proteins / genetics
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Interleukin-3 / metabolism*
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Interleukin-3 / pharmacology
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 2
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Mice
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Mice, Mutant Strains
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Milk Proteins*
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Oncogene Proteins / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptors, Interleukin-3 / metabolism
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STAT5 Transcription Factor
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Signal Transduction / physiology*
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Trans-Activators / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Gab1 protein, mouse
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Homeodomain Proteins
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Interleukin-3
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Intracellular Signaling Peptides and Proteins
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Milk Proteins
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Oncogene Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Receptors, Interleukin-3
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STAT5 Transcription Factor
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Tlx1 protein, mouse
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Trans-Activators
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2
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Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse