enabled a correct prediction of splice junctions 
within the PDGF-R gene. Their overall homology 
and genome organization therefore suggest that 
CSF-IR and PDGF-R were derived from an ancestral 
gene that underwent duplication and subsequent 
divergence. Sequences governing CSF-IR expres- 
sion in trophoblasts might reside within the PDGF- 
R gene, thereby providing a basis for their mutually 
exclusive expression in different cells of the pla- 
centa. A similar genomic organization might be ex- 
pected for the A-type PDGF-R and c-kit genes on 
human chromosome 4. 
III. Receptor Downregulation by CSF-1 and Trans- 
modulation by Protein Kinase C. 
In the absence of ligand, CSF-IR turns over with 
a half-life of 3-4 hours, but CSF-1 binding induces 
receptor internalization and degradation within 
minutes after stimulation. Receptor turnover is also 
accelerated after treatment of cells with agents such 
as phorbol esters that activate protein kinase C 
(PKC). The mechanisms of ligand- and PKC-induced 
degradation were shown to differ by several cri- 
teria. First, a kinase-defective receptor mutant con- 
taining a methionine-for-lysine substitution at its 
ATP-binding site was refractory to ligand but was 
rapidly degraded in response to phorbol esters. 
PUBLICATIONS 
Second, in cells in which PKC was itself down- 
modulated by chronic phorbol ester treatment, re- 
ceptors reexpressed at the cell surface remained 
sensitive to ligand-induced downregulation. Thus 
downregulation requires CSF-IR tyrosine kinase ac- 
tivity (but not PKC), whereas transmodulation de- 
pends on PKC (but not CSF-IR kinase) activity. 
Phorbol ester treatment did not lead to receptor 
phosphorylation but rather induced proteolytic 
cleavage of CSF-IR near its transmembrane domain. 
This resulted in release of the CSF-IR ligand-bind- 
ing domain from the cell and the transient appear- 
ance of a cell-associated 50 kDa fragment repre- 
senting the tyrosine kinase domain. The latter 
polypeptide is probably inactive as an enzyme, be- 
cause it lacks phosphotyrosine, the hallmark of the 
activated CSF-IR kinase. Thus physiologic agents 
that induce PKC in monocytes and macrophages 
should antagonize the CSF-1 response. Because 
CSF-1 functions as a survival factor for mature 
mononuclear phagocytes, transmodulation of CSF- 
IR on activated macrophages may serve to limit 
their life span during an inflammatory response. 
Dr. Sherr is Member of the Department of Tumor 
Cell Biology at St. Jude Children's Research Hospi- 
tal and Professor of Biochemistry at the University 
of Tennessee College of Medicine. 
Articles 
Ashmun, R.A., Look, A.T., Roberts, WM., Roussel, M.F., Seremetis, S., Ohtsuka, M., and Sherr, C.J. 1989. 
Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on 
normal mononuclear phagocytes and on human myeloid leukemic blast cells. Blood 73:827-837. 
Downing, J.R., Roussel, M.F., and Sherr, C.J. 1989. Ligand and protein kinase C downmodulate the colony- 
stimulating factor 1 receptor by independent mechanisms. Mol Cell Biol 9:2890-2896. 
Hampe, A., Shamoon, B.-M., Gobet, M., Sherr, C.J. , and Galibert, F. 1989. Nucleotide sequence and structural 
organization of the human iW5 proto-oncogene. Oncogene Res 4:9-17. 
Roberts, WM., Look, A.T., Roussel, M.F, and Sherr, C.J. 1988. Tandem linkage of human CSF-1 receptor 
(c-fms) and PDGF receptor genes. Cell 55:655-661. 
Roussel, M.F, Downing, J.R., Rettenmier, C.W, and Sherr, C.J. 1988. A point mutation in the extracellular do- 
main of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential. 
Ce// 55:979-988. 
Sherr, C.J. 1988. Thefms oncogene. Biochim Biophys Acta 948:225-243. 
Sherr, C.J. , Ashmun, R.A., Downing, J.R., Ohtsuka, M., Quan, S.G., Golde, D.W, and Roussel, M.F 1989. Inhi- 
bition of colony-stimulating factor-1 activity by monoclonal antibodies to the human CSF-1 receptor. 
B/oo^/ 73:1786-1793. 
Sherr, C.J. , Rettenmier, C.W, and Roussel, M.F. 1988. Macrophage colony-stimulating factor, CSF-1, and its 
proto-oncogene-encoded receptor. Cold Spring Harb Symp Quant Biol 53:521-530. 
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