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 spe 
cialty training in cardiology at the Massachusetts General Hospital. 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. 
DURING embryonic development, tissues 
grow by the rapid proliferation of their con- 
stituent cells. An important mechanism by which 
intricate patterns of embryonic cell growth are 
regulated involves the local production of pro- 
tein growth factors that stimulate cell prolifera- 
tion. In adults the cells of most tissues proliferate 
slowly, dividing at a minimal rate that is just suffi- 
cient to replace senescent cells. However, in a 
few specific situations (for example, after tissue 
injury) the rate of cell proliferation can increase 
dramatically. This exceptionally rapid cell divi- 
sion is similar to embryonic cell proliferation and 
appears to be stimulated by some of the same 
growth factors. 
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 produced 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 con- 
stitute atherosclerotic plaques. Its role in vascu- 
lar proliferation appears to be especially promi- 
nent in the recurrent blockage of coronary 
arteries that occurs after clinical interventions 
such as angioplasty or atherectomy, which are un- 
dertaken in an attempt to restore blood flow 
through vessels narrowed by atherosclerosis. 
PDGF also plays a role in the growth of some tu- 
mors. 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 
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