Growth Control of Myeloid Cells 
Charles J. Sherr, M.D., Ph.D. — Investigator 
Dr. Sherr is also a member of the Department of Tumor Cell Biology at St. Jude Children 's Research 
Hospital and Adjunct Professor of Biochemistry at the University of Tennessee College of Medicine, 
Memphis. He received his medical degree and his Ph.D. degree in immunology from New York University 
School of Medicine, where he studied with Jonathan Uhr. After a pathology residency at Bellevue Hospital 
Center, New York, he joined George Todaro's laboratory at the National Cancer Institute, where he began 
studies on retroviral oncogenes. After 10 years on the staff of the NCI, Dr. Sherr relocated to St. Jude 
Children 's Research Hospital. 
EACH day humans produce billions of blood 
cells, which enter the circulation from their 
sites of origin in the bone marrow. The majority 
are red cells (erythrocytes) , which transport oxy- 
gen, and the remainder are white cells (leuko- 
cytes), which play a vital role in preventing in- 
fection by bacteria, viruses, and other parasites. 
Different classes of white cells carry out special- 
ized functions: macrophages and granulocytes in- 
gest and kill microorganisms, and lymphocytes 
recognize foreign antigens and produce antibod- 
ies to combat them. 
The process of blood cell production (hema- 
topoiesis) is regulated by a group of protein 
growth factors, termed colony-stimulating fac- 
tors (CSFs) or interleukins. These factors stimu- 
late the precursors of mature white cells to form 
colonies in agar composed of differentiated 
blood cell elements and v/ere named for the types 
of colonies they produced. For example, M-CSF 
(or CSF-1) specifically induces macrophage colo- 
nies, G-CSF promotes granulocyte development, 
and GM-CSF stimulates the growth and differen- 
tiation of both types of cells. CSFs, now produced 
in quantity through genetic engineering tech- 
niques, have become part of the clinical arma- 
mentarium and are efficacious in extrinsically 
regulating blood cell production and in height- 
ening host defense against infection. 
Signal Transduction by the CSF-1 Receptor 
The actions of CSFs in supporting cell prolifera- 
tion and survival are mediated through their bind- 
ing to specific receptors expressed on the sur- 
faces of their target cells. The macrophage CSF-1 
receptor (CSF-1 R) consists of an extracellular 
growth factor-binding portion, joined through a 
single membrane-spanning segment to an intra- 
cellular enzymatic domain. Binding of CSF-1 to 
its receptor on the outside of the cell triggers the 
activity of the intracellular enzymatic moiety — a 
kinase — inducing it to add phosphate molecules 
to other proteins. These phosphorylation events 
modify the biochemical behavior of multiple tar- 
get proteins, some of which relay signals to the 
cell nucleus that alter gene expression, DNA syn- 
thesis, and cell division. 
The ability of many cell types to respond to 
CSF- 1 is simply determined by whether they ex- 
press its receptor. By introducing the gene en- 
coding CSF-IR into naive cells, we can sensitize 
them to the stimulatory effects of the growth fac- 
tor. Such manipulations have allowed us to study 
genetically engineered receptor variants for their 
capacity to transduce signals for cell growth or 
differentiation. 
One strategy is to alter different portions of the 
intracellular domain of CSF-IR in order to pin- 
point structural motifs that determine its interac- 
tion with its "downstream" targets. A conse- 
quence has been the development of receptors 
that are impaired in transducing signals through 
certain pathways but not others. In particular in- 
stances the introduction of other complementing 
genes into cells that express partially defective 
receptor mutants has reconstituted full receptor 
activity, thereby providing genetic evidence for 
functional relationships between different gene 
products in signaling pathways. 
Such experiments have revealed that the com- 
binatorial actions of target proteins that bind to, 
or are phosphorylated by, CSF- 1 R can in part de- 
termine the specificity of the biological response 
in different cell types, thereby influencing deci- 
sions governing cell proliferation, survival, and 
fate. 
Oncogenic Potential of CSF-IR 
CSF- 1 R is encoded by the FMS proto-oncogene 
and can be converted by mutations to an "onco- 
protein" capable of inducing tumors. Certain 
mutations in the extracellular domain of CSF-IR 
can mimic the action of CSF-1 and activate the 
receptor kinase in the complete absence of the 
growth factor. The sustained and unregulated sig- 
nals for cell growth that arise from this class of 
mutant receptors might naturally contribute to 
malignancies involving macrophages or their 
bone marrow progenitor cells. 
We have recently used a prospective genetic 
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