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Regulation of the Epidermal Growth Factor Receptor by Growth-modulating Agents: Effects of Staurosporine, a Protein Kinase Inhibitor¹

Genzyme, Boston, Massachusetts [B. F.]; National Cancer Center Research Institute, Cancer Prevention Division, Tokyo, Japan [H. F.]; and University of Chicago, Ben May Institute, Chicago, Illinois [M. R. R.]

Staurosporine is a potent microbial inhibitor of a number of protein kinases, including protein kinase C, cyclic AMP-dependent kinase, and the tyrosine kinase pp60^arc. We have used staurosporine to investigate the role of phosphorylation in the regulation of the epidermal growth factor (EGF) receptor in both human epidermal carcinoma A431 cells and mouse Swiss 3T3 fibroblasts. We report here that staurosporine treatment causes enhancement in high affinity EGF binding and a decrease in the phosphorylation state of the unstimulated receptor at a number of residues, including threonine 669. Staurosporine also antagonizes the inhibition of high affinity EGF binding and the increase in phosphorylation state of the unstimulated EGF receptor by phorbol esters and the calcium ionophore A23187. Staurosporine is an effective inhibitor of the EGF-stimulated receptor tyrosine kinase in vitro and thus does not enhance EGF stimulation of EGF receptor autophosphorylation in vivo. These results suggest that phosphorylation plays a major role in the regulation of the high affinity binding state of the EGF receptor in both unstimulated and mitogenically activated cells.

¹ Supported by National Cancer Institute Awards CA35541 and CA40407 to M. R. R. and a Fulbright Collaborative Research Grant to B. F.

² Former address: Department of Applied Biological Sciences, MIT, Cambridge, MA.

³ To whom requests for reprints should be addressed, at University of Chicago, Ben May Institute, Box 424, 5841 S. Maryland Ave., Chicago, IL 60637.

Received 2/ 3/89. Revised 7/13/89. Revised 10/11/89. Accepted 10/27/89.