Growth Factor-stimulated Cell Proliferation 
designed and produced mutant receptors that 
have normal PDGF-binding domains but defec- 
tive kinase domains. When these mutants are in- 
troduced into cells that have normal receptors, a 
dimer (heterodimer) is formed between the nor- 
mal and kinase-defective receptors. The normal 
and mutant receptors in the heterodimer com- 
plex cannot phosphorylate each other and cannot 
transmit the signals required to initiate cell 
growth. These experiments prove that formation 
of a dimer consisting of two normal receptors is 
required for proper functioning and signal trans- 
duction of the receptor. By introducing mutant 
receptors into specific tissues of animals we hope 
to be able to block the function of the normal 
receptors and assess the role of PDGF in physio- 
logical 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 identified 
one of these molecules, phosphatidylinositol-3 
kinase (PI3 kinase), that appears to play an im- 
portant role in PDGF-stimulated proliferation. 
Other investigators have found that PI3 kinase is 
also important in the cell transformation caused 
by some mammalian oncogenic viruses. Using the 
receptor as a probe, we recently purified the PI3 
kinase and cloned the gene for this signaling mol- 
ecule. We hope that by studying the interaction 
of the receptor and PI 3 kinase we can understand 
an important set of reactions that are involved in 
regulating cell growth. 
We recently have begun to study the fibroblast 
growth 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 the setting of 
atherosclerotic 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. 
The long-range goal of these studies is to probe 
the role of growth 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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