Abstract
The receptor for epidermal growth factor (EGF) is a 170,000–180,000 molecular weight single-chain glycoprotein of 1,186 amino acids1. Its sequence suggests that it has an external EGF-binding domain, formed by the NH2-terminal 621 amino acids, linked to a cytoplasmic region by a single membrane-spanning segment1. In the cytoplasmic portion, starting 50 residues from the membrane, there is a 250-residue stretch similar to the catalytic domain of the src gene family of retroviral tyrosine protein kinases1, and, indeed, a tyrosine-specific protein kinase activity intrinsic to the receptor is stimulated when EGF is bound2–5. Increased tyrosine phosphorylation of cellular proteins, detected in A431 cells following EGF binding6,7, may be important in the mitogenic signal pathway. Tumour promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA), counteract this increase8,9, as well as causing loss of a high affinity class of EGF binding sites9. The major receptor for TPA has been identified as the serine/threonine-specific Ca2+/phospholipid-dependent diacylglycerol-activated protein kinase, protein kinase C10–14. By substituting for diacylglycerol, TPA stimulates protein kinase C. Protein kinase C phosphorylates purified EGF receptor at specific sites, and this reduces EGF-stimulated tyrosine protein kinase activity8. TPA treatment of A431 cells increases serine and threonine phosphorylation of the EGF receptor at the same sites8,15, which suggests that the reduction of EGF receptor kinase activity in TPA-treated cells is a consequence of the receptor's phosphorylation by the kinase. We have attempted to identify these phosphorylation sites and show here that protein kinase C phosphorylates threonine 654 in the human EGF receptor. This threonine is in a very basic sequence nine residues from the cytoplasmic face of the plasma membrane in the region before the protein kinase domain; it is thus in a position to modulate signalling between this internal domain and the external EGF-binding domain.
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References
Ullrich, A. et al. Nature 309, 418–425 (1984).
Cohen, S., Carpenter, G. & King, L. E. J. biol. Chem. 255, 4834–4842 (1980).
Ushiro, H. & Cohen, S. J. biol. Chem. 255, 8363–8365 (1980).
Buhrow, S. A., Cohen, S. & Staros, J. V. J. biol. Chem. 257, 4019–4022 (1981).
Cohen, S. et al. J. biol. Chem. 257, 1523–1531 (1982).
Hunter, T. & Cooper, J. A. Cell 24, 741–752 (1981).
Gill, G. N. & Lazar, C. S. Nature 293, 305–307 (1981).
Cochet, C. et al. J. biol. Chem. 259, 2553–2558 (1984).
Friedman, B. et al. Proc. natn. Acad. Sci. U.S.A. 81, 3034–3038 (1984).
Niedel, J. E., Kuhn, L. J. & Vandenbark, G. R. Proc. natn. Acad. Sci. U.S.A. 80, 36–40 (1983).
Castagna, M. et al. J. biol. Chem. 257, 7847–7851 (1982).
Leach, K. L., James, M. L. & Blumberg, P. M. Proc. natn. Acad. Sci. U.S.A. 80, 4208–4212 (1983).
Ashendel, C. L., Staller, J. M. & Boutwell, R. K. Biochem. biophys. Res. Commun. 111, 340–345 (1983).
Parker, P., Stabel, S. & Waterfield, M. D. EMBO J. 3, 953–959 (1984).
Iwashita, S. & Fox, C. F. J. biol. Chem. 259, 2559–2567 (1984).
Downward, J. et al. Nature 307, 521–527 (1984).
Yamamoto, T. et al. Cell 35, 71–78 (1983).
Nishizuka, Y. et al. Adv. cyclic Nucleotide Res. 9, 209–220 (1978).
Takai, Y. et al. J. biol. Chem. 254, 3692–3695 (1979).
Wise, B. C. et al. J. biol. Chem. 257, 8489–8495 (1982).
Ramachandran, C. et al. J. biol. Chem. (in the press).
Turner, R. S. et al. J. Neurochem. (in the press).
Sano, K. et al. J. biol. Chem. 258, 2010–2013 (1983).
Sawyer, S. T. & Cohen, S. Biochemistry 20, 6280–6286 (1981).
Kraft, A. S. & Anderson, W. B. Nature 301, 621–623 (1983).
Lee, L.-S. & Weinstein, I. B. Science 202, 313–315 (1978).
Shoyab, M., DeLarco, J. E. & Todaro, G. J. Nature 279, 387–391 (1979).
Salomon, D. S. J. biol. Chem. 256, 7958–7966 (1981).
King, A. C. & Cuatrecasas, P. J. biol. Chem. 257, 3053–3060 (1982).
Hunter, T. & Sefton, B. M. Proc. natn. Acad. Sci. U.S.A. 77, 1311–1315 (1980).
Kikkawa, U. et al. J. biol. Chem. 257, 13341–13348 (1982).
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Hunter, T., Ling, N. & Cooper, J. Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. Nature 311, 480–483 (1984). https://doi.org/10.1038/311480a0
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DOI: https://doi.org/10.1038/311480a0
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