Growth Factor-stimulated Cell Proliferation 
tors is required for proper functioning and signal 
transduction of the receptor. By introducing mu- 
tant receptors into specific tissues of animals we 
hope to be able to block the function of the nor- 
mal receptors and assess the role of PDGF in phys- 
iological processes and in disease states. 
When the dimerized receptor is phosphory- 
lated, the second major step in signal transduc- 
tion occurs. The phosphorylated receptor physi- 
cally binds to signaling molecules that are inside 
the cell. We have recently found that the interac- 
tion between the receptor and signaling mole- 
cules occurs at the phosphorylation sites on the 
receptor. Using information about the structures 
of these sites, we are designing ways to disrupt 
the interaction between the receptors and the sig- 
naling molecules. We are also using the receptors 
as a tool for discovering previously unidentified 
signaling molecules that mediate that prolifera- 
tive response to PDGF. Recently we have identi- 
fied one of these molecules, phosphatidylinositol 
3-kinase (PI 3-kinase), that appears to play an im- 
portant role in PDGF-stimulated proliferation. 
Other investigators have found that PI 3-kinase is 
also important in the cell transformation caused 
by some viruses that cause cancer in animals. Us- 
ing the receptor as a probe, we recently purified 
the PI 3-kinase and cloned the gene for this signal- 
ing molecule. We hope that by studying the inter- 
action of the receptor and PI 3-kinase we can un- 
derstand an important set of reactions that are 
involved in regulating cell growth. 
We recently have begun to study the fibroblast 
grovvT:h factors (FGF). These factors appear to 
play important roles in the earliest stages of em- 
bryogenesis and in angiogenesis (the formation 
of new blood vessels) . The development of new 
vessels can be beneficial (e.g., in offsetting ath- 
erosclerotic narrowing of blood vessels in the 
heart) or deleterious (e.g., in the formation of 
new vessels that supply nutrients to tumors or in 
the vascular proliferation that occurs in the eyes 
of diabetic patients) . We have identified some of 
the FGF receptors and are now examining their 
mechanisms of action. This work on FGF recep- 
tors is supported by a grant from the National In- 
stitutes of Health. 
The long-range goal of these studies is to probe 
the role of grov^h factors in normal embryonic 
development, in tissue repair, and in prolifera- 
tive diseases. Using the tools of molecular biol- 
ogy, cell biology, and protein chemistry, we and 
other research groups are identifying the factors, 
receptors, and regulatory molecules involved in 
these processes. Studies of the spatial and tem- 
poral distribution of the growth factors and re- 
ceptors in normal and diseased tissues will pro- 
vide insight into the function of these molecules. 
By understanding the molecular details of the 
protein-protein interactions involved in growth 
factor action, it may be possible to devise new 
therapeutic strategies to treat proliferative 
diseases. 
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