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Biochemical and genetic characterization of multiple splice variants of the
Flt3 ligand
T McClanahan, J Culpepper, D Campbell, J Wagner, K Franz-Bacon, J Mattson, S Tsai, J Luh, MJ Guimaraes, MG Mattei, O Rosnet, D Birnbaum and CH Hannum
DNAX Research Institute of Molecular and Cellular Biology, Department of
Molecular Biology, Palo Alto, CA 94304, USA.
We have performed a comprehensive analysis of cell lines and tissues to
compare and contrast the expression patterns of Flt3 ligand (FL), c-Kit
ligand (KL), and macrophage colony-stimulating factor as well as their
receptors, Flt3, c-Kit, and c-Fms. The message for FL is unusually
ubiquitous, whereas that of its receptor is quite restricted, apparently
limiting the function of the ligand to fetal development and early
hematopoiesis. We have also sequenced a mouse FL genomic clone, revealing
how the three splice variant FL mRNAs that we have isolated arise. The
chromosomal location of the FL gene has been mapped, by in situ
hybridization, to chromosome 7 in mouse and chromosome 19 in human. Natural
FL protein has been purified from a stromal cell line and shown to be a 65
kD nondisulfide-linked homodimeric glycoprotein comprised of 30 kD
subunits, each containing 12 kD of N- and O-linked sugars. Pulse-chase
experiments show that one of the splice variants (T110) is responsible for
producing the bulk of soluble FL, but only after it has first been
expressed at the cell surface as a membrane- bound form. The other
splice-variant forms produce molecules that are either obligatorily soluble
(T169) or membrane-bound but released only very slowly (T118). Finally,
even though most cell lines express some amount of FL mRNA, we found that
very little FL protein is actually made, with T cells and stromal cells
being the major producers. The data suggests that FL plays its roles over
very short distances, perhaps requiring cell-cell contact.
Volume 88,
Issue 9,
pp. 3371-3382,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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