Growth Factor-stimulated Cell Proliferation 
Lewis T. Williams, M.D., Ph.D. — Investigator 
Dr. Williams is also Professor of Medicine at the University of California, San Francisco. He received his 
undergraduate degree from Rice University and his M.D. and Ph.D. degrees from Duke University, where 
he studied with Robert Lefkowitz. He then completed a clinical residency in internal medicine and 
specialty training in cardiology at Massachusetts General Hospital, Boston. Before joining the faculty at 
UCSF, he was Assistant Professor of Medicine at Harvard Medical School. Among his honors is the 
Outstanding Young Investigator Award of the American Federation for Clinical Research. 
POLYPEPTIDE groAvth factors regulate the pro- 
liferation and migration of cells in the devel- 
oping tissues of embryonic animals. The actions 
of these factors appear to be recapitulated in 
adults when damaged or senescent tissues are re- 
paired. Our research group is investigating the 
action of platelet-derived growth factor (PDGF) . 
This potent growth factor for fibroblast and 
smooth muscle cells is found in platelets and is 
released at sites of tissue injury. PDGF is also pro- 
duced by other tissues, including endothelial 
cells that line the inner surfaces of blood vessels. 
In this context PDGF is likely to play a major role 
in stimulating the proliferation of smooth muscle 
cells that constitute atherosclerotic plaques. Its 
role in vascular proliferation appears to be espe- 
cially prominent in the recurrent blockage of cor- 
onary arteries that occurs after clinical interven- 
tions such as angioplasty or atherectomy, which 
are undertaken in an attempt to restore blood 
flow through vessels narrowed by atherosclero- 
sis. PDGF also plays a role in the growth of some 
tumors. At least one monkey sarcoma is caused by 
the aberrant production of PDGF, which stimu- 
lates the tumor cells to grow in an uncontrolled 
fashion. 
Like other growth factors, PDGF acts on cells 
by first binding to specific receptor sites located 
on the cell surface. This interaction of PDGF with 
its receptor is transmitted as a signal across the 
cell membrane and triggers a series of complex 
reactions inside the cell that culminate in DNA 
synthesis and cell division. To study the mecha- 
nism of signal transmission by the PDGF receptor, 
we purified the receptor from mouse cells, 
cloned the gene that encodes the mouse receptor 
protein, expressed this receptor in cells that nor- 
mally lack PDGF receptors, and demonstrated 
that this expressed receptor mimics the actions of 
native PDGF receptors and mediates all of the 
known responses to PDGF. 
The PDGF receptor is anchored at the surface 
of the cell and is oriented so that approximately 
half of the receptor, the PDGF-binding domain, is 
located outside the cell, and the other half of the 
receptor is located inside the cell. The receptor 
appears to consist of several distant regions, 
termed domains, that have distinct functions. Us- 
ing the cloned gene for the receptor, we can pro- 
duce individual domains of the receptor protein 
and study the functions of these domains. For ex- 
ample, we have produced receptor fragments 
that contain the PDGF-binding domain but lack 
the other portions of the molecule. To localize 
more precisely the portion of the receptor that is 
essential for binding PDGF, we are now prepar- 
ing even smaller versions of the binding domain 
by deleting portions of the molecule. When a 
minimal domain for binding is defined, we will 
study the three-dimensional structure of this sim- 
plified molecule and use this information to de- 
sign agents that can block the binding of PDGF to 
its receptor. These agents should function as 
blockers of the actions of PDGF and will facilitate 
the study of the role of PDGF in atherosclerosis 
and cancer. 
One of the major problems in growth factor 
research has been to determine how the portion 
of the receptor inside the cell senses that the bind- 
ing domain on the outside of the cell has inter- 
acted with PDGF. We have recently found that 
the transmission of the signal from the outside 
domain to the inside of the cell involves two ma- 
jor steps. First, when a receptor molecule binds 
PDGF, the receptor pairs with another identical 
receptor molecule to form a receptor dimer. Each 
of the two receptor molecules in the dimeric 
complex phosphorylates its partner, thereby 
modifying the partner. The phosphorylation reac- 
tion results in the addition of a phosphate group 
to the partner and is accomplished by a region of 
the receptor termed the kinase domain. We have 
designed and produced mutant receptors that 
have normal PDGF-binding domains but have de- 
fective kinase domains. When these mutants are 
introduced into cells that have normal receptors, 
a dimer (heterodimer) is formed between the 
normal and kinase-defective receptors. The nor- 
mal and mutant receptors in the heterodimer 
complex cannot phosphorylate each other and 
cannot transmit the signals required to initiate 
cell growth. These experiments prove that forma- 
tion of a dimer consisting of two normal recep- 
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