Alternative titles; symbols
HGNC Approved Gene Symbol: FLT3LG
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,474,215-49,486,231 (from NCBI)
Dendritic cells (DCs) provide the key link between innate and adaptive immunity by recognizing pathogens and priming pathogen-specific immune responses. FLT3LG controls the development of DCs and is particularly important for plasmacytoid DCs and CD8 (see 186910)-positive classical DCs and their CD103 (ITGAE; 604682)-positive tissue counterparts (summary by Sathaliyawala et al., 2010).
FMS-related tyrosine kinase-3 (FLT3; 136351) is a tyrosine kinase receptor structurally related to macrophage colony-stimulating factor (CSF1; 120420) and to mast cell growth factor receptor (KIT; 164920). From a murine T-cell line, Lyman et al. (1993) cloned a novel hematopoietic growth factor that is a ligand for FLT3. Lyman et al. (1994) used a fragment of the murine cDNA to clone the human FLT3 ligand, which is similar in structure to the murine protein and shares 72% amino acid identity. Northern blot analysis showed widespread expression of FLT3 ligand mRNA transcripts in human tissues.
Hannum et al. (1994) isolated a soluble protein that showed FL activity from medium conditioned by mouse thymic stromal cells. By sequencing peptides and screening thymic stromal cell lines, they cloned splice variants of mouse and human FL. The deduced 235- and 245-amino acid human isoforms differ in their C-terminal segments, with the shorter protein containing a unique transmembrane domain. The N terminus of both isoforms contains a signal peptide followed by a cytokine domain related to KIT ligand (KITLG; 184745) and macrophage colony-stimulating factor (CSF1; 120420). The cytokine domain also has N-glycosylation sites. Northern blot analysis showed widespread expression in mouse and human tissues, with highest levels in spleen and lung. The major human transcript was 1.6 kb. High expression was also detected in mouse and human stromal cell lines, with highest levels in T-cell lines and peripheral blood mononuclear cells.
Lyman et al. (1993) found that Flt3 ligand stimulated proliferation of hematopoietic progenitor cells isolated from mouse fetal liver or adult mouse bone marrow.
Hannum et al. (1994) showed that transfection of COS cells with mouse and human FL containing the C-terminal transmembrane domain resulted in secretion of a soluble protein with FL activity. Assays of C-terminally truncated FL proteins confirmed that the N-terminal half conferred FL activity. Recombinant protein produced by either mouse fibroblasts or E. coli induced tyrosine autophosphorylation of Flt3 on mouse cells. The purified protein enhanced the response of mouse stem cells and primitive human progenitor cells to other growth factors, such as IL3 (147740), IL6 (147620), and granulocyte-macrophage colony-stimulating factor (CSF2; 138960), and it also stimulated fetal thymocytes. Hannum et al. (1994) concluded that FL enhances the response of stem and primitive progenitor cells to other growth factors to generate all myeloid lineages except erythroid cells.
Sathaliyawala et al. (2010) found that the Mtor (FRAP1; 601231) inhibitor rapamycin impaired mouse Flt3l-driven DC development in vitro, with plasmacytoid DCs and classical DCs most profoundly affected. Depletion of the Pi3k (see 601232)-Mtor negative regulator Pten (601728) facilitated Flt3l-driven DC development in culture. Targeting Pten in DCs in vivo caused expansion of Cd8-positive and Cd103-positive classical DCs, which could be reversed by rapamycin. Increased Cd8-positive classical DC numbers caused by Pten deletion correlated with increased susceptibility to Listeria infection. Sathaliyawala et al. (2010) concluded that PI3K-MTOR signaling downstream of FLT3L controls DC development, and that restriction by PTEN ensures optimal DC numbers and subset composition.
Hannum, C., Culpepper, J., Campbell, D., McClanahan, T., Zurawski, S., Bazan, J. F., Kastelein, R., Hudak, S., Wagner, J., Mattson, J., Luh, J., Duda, G., and 14 others. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 368: 643-648, 1994. [PubMed: 8145851] [Full Text: https://doi.org/10.1038/368643a0]
Lyman, S. D., James, L., Johnson, L., Brasel, K., de Vries, P., Escobar, S. S., Downey, H., Splett, R. R., Beckmann, M. P., McKenna, H. J. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 83: 2795-2801, 1994. [PubMed: 8180375]
Lyman, S. D., James, L., Vanden Bos, T., de Vries, P., Brasel, K., Gliniak, B., Hollingsworth, L. T., Picha, K. S., McKenna, H. J., Splett, R. R., Fletcher, F. A., Maraskovsky, E., Farrah, T., Foxworthe, D., Williams, D. E., Beckmann, M. P. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 75: 1157-1167, 1993. [PubMed: 7505204] [Full Text: https://doi.org/10.1016/0092-8674(93)90325-k]
Sathaliyawala, T., O'Gorman, W. E., Greter, M., Bogunovic, M., Konjufca, V., Hou, Z. E., Nolan, G. P., Miller, M. J., Merad, M., Reizis, B. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33: 597-606, 2010. [PubMed: 20933441] [Full Text: https://doi.org/10.1016/j.immuni.2010.09.012]