title: Axl/Gas6 pathway positively regulates FLT3 activation in human natural killer cell development.
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.
authors.affiliation: The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Il-Kyoo
authors.initials: IK
authors.lastname: Park
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D018952:Antigens, CD34; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D051941:fms-Like Tyrosine Kinase 3; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C497970:FLT3 protein, human; C000722289:AXL protein, human
keywords: Axl; CD34+ HPC; FMS-like tyrosine kinase 3 (FLT3); NK cell