FMS-LIKE TYROSINE KINASE-3 CATALYTIC DOMAIN CAN TRANSDUCE A PROLIFERATIVE SIGNAL IN FDC-P1 CELLS THAT IS QUALITATIVELY SIMILAR TO THE SIGNAL DELIVERED BY C-FMS
- Author(s)
- Rossner, MT; McArthur, GA; Allen, JD; Metcalf, D;
- Details
- Publication Year 1994-05,Volume 5,Issue #5,Page 549-555
- Journal Title
- CELL GROWTH & DIFFERENTIATION
- Publication Type
- Journal Article
- Abstract
- full length clone of murine fms-like tyrosine kinase 3 [flt3, also known as fetal liver kinase 2 (flk2)] was constructed from sequences obtained from a brain complementary DNA (cDNA) library and from cDNA prepared from the cell line Tikaut. In the absence of a ligand to study the function of Flt3, a chimeric molecule was constructed comprising the extracellular domain of murine c-Fms and the transmembrane and cytoplasmic domains of Flt3. A plasmid encoding the chimeric receptor was cotransfected along with a plasmid conferring neomycin resistance into FDC-P1 cells that do not normally express c-fms or flt3 and require granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 for growth. Two types of clones were obtained following selection in CM-CSF and G418. Two of seven clones had the capacity for M-CSF-dependent colony formation in semisolid medium, indicating that the cytoplasmic domain of Flt3 can transduce a proliferative signal. From the remaining clones, M-CSF-dependent clonogenic cells could be selected by prior bulk liquid culture in M-CSF. It has been shown previously that the GM-CSF-dependent proliferative capacity is strongly inhibited by M-CSF in FDC-P1 cells engineered to express full length c-fms. This phenomenon was also observed with FD/fms-flt3 cells that were clonogenic in M-CSF. Stimulation of FD/fms or FD/fms-flt3 cells in liquid culture by M-CSF caused differentiation of a small proportion of cells along the myelomonocytic pathway which was enhanced by the combination of M-CSF and GM-CSF. The similarity of the response of cells bearing either c-Fms or the Fms/Flt3 chimeric receptor to stimulation by M-CSF suggests that Flt3 and c-Fms function through similar signaling pathways.
- Publisher
- AMER ASSOC CANCER RESEARCH
- Keywords
- COLONY-STIMULATING FACTOR; HEMATOPOIETIC STEM-CELLS; GROWTH-FACTOR; MURINE MACROPHAGES; MOLECULAR-CLONING; SI-LOCUS; RECEPTOR; EXPRESSION; GENE; KIT
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Creation Date: 1994-05-01 12:00:00