Signal Transduction by the Epidermal Growth 
Factor Receptor 
Roger J. Davis, Ph.D. — Assistant Investigator 
Dr. Davis is also Associate Professor in the Program in Molecular Medicine and the Department 
of Biochemistry and Molecular Biology at the University of Massachusetts Medical School. He received 
his undergraduate and graduate education at Cambridge University and was a postdoctoral fellow 
with Michael Czech at the University of Massachusetts. 
CELLULAR proliferation is a highly regulated 
process. During embryonic development, 
rapid cell growth is required to form the tissues 
of the body. In contrast, cellular proliferation in 
adults is slow, primarily serving to replace senes- 
cent cells. Adults, however, retain a limited ca- 
pacity for rapid growth — for example, during 
wound healing. Regulation of this proliferative 
capacity is critically important. Errors in growth 
control can result in a variety of diseases, includ- 
ing cancer. 
The local production of protein growth factors 
is an important mechanism that can account for 
the control of cellular proliferation. Our research 
group is investigating the action of a family of 
peptides that includes epidermal growth factor 
(EGF) and transforming growth factor-a (TGF- 
a). These agents are synthesized as cell surface 
glycoproteins that are split to release small solu- 
ble peptides. Both the membrane-bound precur- 
sor and the diffusible peptides are biologically 
active and bind to specific receptor molecules 
located at the surface of responsive cells. Secre- 
tion of these peptide growth factors contributes 
to the rapid growth of some tumors. 
The long-term goal of this laboratory is to un- 
derstand the molecular basis for the control of 
cellular proliferation by the EGF receptor. It is 
known that the binding of growth factors to this 
receptor at the cell surface triggers a complex 
series of chemical reactions that lead to DNA syn- 
thesis within the nucleus and to cell division. 
However, the molecular details of the signaling 
pathways utilized by the receptor are poorly 
understood. 
Regulation of EGF Receptor Function 
The EGF receptor is a glycoprotein consisting 
of an extracellular domain that binds growth fac- 
tor, a membrane-spanning domain, and a cyto- 
plasmic domain. The cytoplasmic domain is an 
enzyme, tyrosine kinase, that causes the covalent 
attachment of phosphate to tyrosine components 
of substrate proteins (phosphorylation). The 
binding of EGF to the receptor's extracellular do- 
main causes an increase in the tyrosine kinase ac- 
tivity of the cytoplasmic domain. EGF also causes 
the receptor to aggregate and to associate tran- 
siently with intracellular regulatory molecules to 
form a signal transduction complex. We are study- 
ing these interactions and investigating the con- 
sequences of the phosphorylation process. 
The ability of EGF to increase the tyrosine ki- 
nase activity of its receptor is blocked when cells 
are incubated with a tumor promoter or with 
other growth factors. Under these conditions, the 
EGF receptor is itself phosphorylated at multiple 
serine and threonine residues. We are investigat- 
ing the significance of this phosphorylation. Our 
approach is to construct receptors with point 
mutations at the sites of phosphorylation, using 
recombinant DNA technology. These studies have 
demonstrated that the phosphorylation of a single 
threonine residue blocks the ability of EGF to 
stimulate the receptor's tyrosine kinase activity. 
Phosphorylation also alters the internalization of 
the receptor. We are investigating the structural 
basis for the effects of phosphorylation on the 
regulation of EGF receptor function. These stud- 
ies are supported by a grant from the National 
Institutes of Health. 
Signaling by the EGF Receptor 
A principal question that we must answer to 
understand the mechanism of signal transduction 
by the EGF receptor is how a signal that is initi- 
ated at the cell surface can be transmitted to the 
nucleus to cause DNA replication. One class of 
regulatory molecules that could account for this 
process is the protein kinases. We are focusing 
our research on one subclass of these enzymes 
that cause the phosphorylation of proline-rich 
target sequences in substrate proteins. Examples 
are represented by the mitogen-activated protein 
kinases and the cyclin-dependent protein ki- 
nases. Each of these types of protein kinases exists 
in multiple forms as part of an extended family of 
enzymes that are regulated by growth factors and 
by the cell cycle. We are investigating the struc- 
ture of additional members of this family by mo- 
lecular cloning. 
Substrates for these growth factor-regulated 
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