Mechanism of Action of Polypeptide Growth Factors 
Desensitization of the EGF Receptor 
When A43 1 cells are treated with large doses of 
EGF, washed, and subsequently rechallenged 
with EGF, they fail to respond to the growth fac- 
tor. This phenomenon is known as desensitiza- 
tion. Our studies have shown that when the EGF 
jxceptor becomes desensitized, it is no longer in- 
ternalized into the cells, and EGF no longer stimu- 
lates phosphatidylinositol metabolism. This EGF- 
induced desensitization is specific for the EGF 
receptor, as the responsiveness of other receptors 
is not decreased after EGF treatment. 
The EGF receptor itself is a monomeric pro- 
tein, a single chain. Upon binding of EGF to its 
receptor, two of the receptor monomers come 
together to form an EGF receptor dimer. This 
dimer is the form that is active in signal transduc- 
tion. Desensitized EGF receptors cannot undergo 
this EGF-induced dimerization. As a result, they 
cannot transduce the hormonal signal to the inte- 
rior of the cell. 
Evidence suggests that the desensitization of 
the EGF receptor results from its phosphorylation 
by a protein kinase. We have identified a protein 
kinase in A431 cell cytosol that is activated by 
EGF and appears to be involved in receptor de- 
sensitization. The kinase catalyzes the phosphor- 
ylation of the EGF receptor in vitro. Consistent 
with what has been observed in whole cells, 
phosphorylation of EGF receptor monomers by 
this kinase leads in vitro to an inhibition of the 
ability of the phosphorylated monomers to di- 
merize. The kinase phosphorylates the EGF re- 
ceptor on a serine residue in the second half of 
the receptor molecule. Using techniques of mo- 
lecular biology, we plan to alter this site and 
study the effect of this mutation on the function 
of the EGF receptor. 
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