Abstract
Activation of the fibromyalgia syndrome-like tyrosine kinase 3 (FLT3) by its ligand, FLT3 ligand (FL), strongly augments the development of natural killer (NK) cells from human CD34⁺ hematopoietic progenitor cells (HPCs) in the presence of IL-15, compared with NK-cell development in the presence of IL-15 alone. In this study, we observed that blocking the receptor tyrosine kinase Axl/Gas6 pathway with a soluble Axl-IgG1 Fc fusion protein (Axl-Fc) in the presence of FL significantly diminished the absolute number of CD3⁻ CD56⁺ NK cells derived from human CD34⁺ HPCs. Axl-Fc reduced the expression levels of the IL-2/15 receptor β chain (CD122) and γ chain (CD132) induced by activation of FLT3 and consequently reduced the frequency of NK precursor cells responding to IL-15. Furthermore, Axl-Fc diminished FL-induced FLT3 phosphorylation and impeded the physical interaction between Axl and FLT3 in CD34⁺ HPCs. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK-cell development at least in part via its positive regulatory effect on FLT3 signaling in CD34⁺ HPCs.
Keywords:
Axl; CD34+ HPC; FMS-like tyrosine kinase 3 (FLT3); NK cell.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antigens, CD34 / metabolism
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Axl Receptor Tyrosine Kinase
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cells, Cultured
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / immunology*
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Humans
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / immunology
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Immunoglobulin Fc Fragments / metabolism*
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Intercellular Signaling Peptides and Proteins / metabolism*
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Interleukin Receptor Common gamma Subunit / genetics
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Interleukin Receptor Common gamma Subunit / metabolism
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Interleukin-15 / immunology
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Interleukin-2 Receptor beta Subunit / genetics
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Interleukin-2 Receptor beta Subunit / metabolism
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Lymphocyte Activation / drug effects
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / immunology
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Receptor Protein-Tyrosine Kinases / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / immunology
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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Antigens, CD34
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Immunoglobulin Fc Fragments
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Intercellular Signaling Peptides and Proteins
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Interleukin Receptor Common gamma Subunit
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Interleukin-15
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Interleukin-2 Receptor beta Subunit
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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growth arrest-specific protein 6
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FLT3 protein, human
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Receptor Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Axl Receptor Tyrosine Kinase
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AXL protein, human