Regulation of EGF Receptor and Transforming Growth Factor-Alpha Expression

  • Jeffrey E. Kudlow
  • Jeffrey D. Bjorge
  • Michael S. Kobrin
  • Andrew J. Paterson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 234)


In 1957, Salmon and Daughaday demonstrated the presence of a sulfation factor in the serum, whose activity was stimulated by growth hormone1 It is now known that this activity is primarily composed of insulin-like growth factor-I (IGF-I)2 This finding demonstrated a principle upon which our laboratory has focused; that is, that a wide variety of hormones whose initial mechanisms of action are diverse, can stimulate growth through pathways involving growth factors as intermediates. This concept arose out of the finding that protein tyrosine kinases are intimately associated with growth regulation. The first example of a relationship between tyrosine kinases and growth regulation was the product of the src oncogene of the Rous sarcoma virus, pp60src. This oncogene is responsible for the aberrant growth of cells transformed by the virus. Since that time, several oncogenes have been shown to code for highly homologous tyrosine kinases but in addition, several growth factor receptors have been shown by direct sequence analysis to be src-related tyrosine specific protein kinases including the receptors for epidermal growth factor (EGF), platelet derived growth factor (PDGF), IGF-I, insulin, and colony stimulating factor-I3–6. The cDNA’s for all of these receptors have been cloned and many structure-function relationships within these receptors have been established using techniques such as site directed mutagenesis. These studies have strengthened the general concept that the growth response to growth factors is mediated by growth factor dependent, tyrosine specific protein kinases.


Epidermal Growth Factor Receptor Epidermal Growth Factor Phorbol Ester Pituitary Cell Epidermal Growth Factor Receptor Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Daughaday, W.H., Hall, K., Raben, M.S., Salmon Jr, W.D., Van den Brande, J.L., Van Wyk, J.J., Somatomedin: proposed designation for sulphation factor, Nature 235: 107–110 (1972)PubMedCrossRefGoogle Scholar
  2. 2.
    Klapper, D.G., Svoboda, M.E., Van Wyk, J.J., Sequence analysis of somatomedin-C: Confirmation of identity with insulin-like growth factor I. Endocrinology 112: 2215–2223 (1983)PubMedCrossRefGoogle Scholar
  3. 3.
    Salomon, D.S.. Perroteau, I., Growth factors in cancer and their relationship to oncogenes, Cancer Investigation 4: 43–60 (1986)CrossRefGoogle Scholar
  4. 4.
    Goustin, A.S., Leof, E.B., Shipley, G.D., Moses, H.L., Growth factors in cancer. Cancer Research 46: 1015–1029Google Scholar
  5. 5.
    Weinstein, B.I., Growth factors, oncogenes and multistage carcinogenesis. J. Cell. Biochem. 33: 213–224 (1987)PubMedCrossRefGoogle Scholar
  6. 6.
    Hunter, T., A thousand and one protein kinases, Cell 50: 821–822 (1987)CrossRefGoogle Scholar
  7. 7.
    Bravo, R., Burckhardt, J., Curran, T., and Muller, R. Stimulation and inhibition of growth by EGF in different A431 cell clones is accompanied by the rapid induction of c-fos and c-myc protooncogenes, EMBO J. 4: 1193–1197 (1985).PubMedGoogle Scholar
  8. 8.
    Murdoch, G.H., Waterman, M., Evans, R.M., and Rosenfeld, M.G. Molecular mechanisms of phorbol ester, thyrotropin-releasing hormone, and growth factor stimulation of prolactin gene transcription, J. Biol. Chem. 260: 11852–11858 (1985).PubMedGoogle Scholar
  9. 9.
    Elder, P.K., Schmidt, L.J., Ono, T., and Getz, M.J. Specific stimulation of actin gene transcription by epidermal growth factor and cycloheximide, Proc. Natl. Acad. Sci. U.S.A. 81: 7476–7480 (1984).PubMedCrossRefGoogle Scholar
  10. 10.
    Kelly, K., Cochran, B.H., Stiles, C.D., and Leder, P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor, Cell 35: 603–610 (1983).PubMedCrossRefGoogle Scholar
  11. 11.
    Greenberg, M.E., and Ziff, E.B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene, Nature 311: 433–438 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    Muller, R., Bravo, R., Burckhardt, J., and Curran, T. Induction of cfos gene and protein by growth factors precedes activation of cmyc, Nature 312: 716–720 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    Kudlow, J.E., Khosravi, M.J., Kobrin, M.S., Mak, W.W. Inability of anti-epidermal growth factor receptor monoclonal antibody to block “autocrine” growth stimulation in transforming growth factor-secreting melanoma cells, J. Biol. Chem. 259: 11895–11900 (1984)PubMedGoogle Scholar
  14. 14.
    Kudlow, J.E., Cheung, C.-Y. M., and Bjorge, J.D. Epidermal growth factor stimulates the synthesis of its own receptor in a human breast cancer cell line, J. Biol. Chem. 261: 4134–4138 (1986).Google Scholar
  15. 15.
    Clark, A.J.L., Ishii, S., Richert, N., Merlino, G.T., and Pastan, I. Epidermal growth factor regulates the expression of its own receptor, Proc. Natl. Acad. Sci. U.S.A. 82: 8374–8378 (1985).CrossRefGoogle Scholar
  16. 16.
    Earp, H.S., Austin, K.S., Blaisdell, J., Rubin, R.A., Nelson, K.G., Lee, L.W., and Grisham, J.W. Epidermal growth factor (EGF) stimulates EGF receptor synthesis, J. Biol. Chem. 261: 4777–4780 (1986).PubMedGoogle Scholar
  17. 17.
    Takai, Y., Kikkawa, U., Kaibuchi, K., and Nishizuka, Y. Membrane phospholipid metabolism and signal transduction for protein phosphorylation, Advances in Cyclic Nucl. Phosph. Res. 18: 119–158 (1984).Google Scholar
  18. 18.
    Berridge, M.J. Inositol trisphosphate and diacylglycerol as second messengers, Biochem. J. 220: 345–360 (1984).PubMedGoogle Scholar
  19. 19.
    Sawyer, S.T., and Cohen, S. Enhancement of calcium uptake and phosphatidylinositol turnover by epidermal growth factor in A–431 cells, Biochemistry 20: 6280–6286 (1981).PubMedCrossRefGoogle Scholar
  20. 20.
    Smith, K.B., Losonczy, I., Sahai, A., Panneerselvam, M., Fehnel, P., and Salomon, D.S. Effect of 12-0-tetradecanoylphorbol-l3–acetate (TPA) on the growth inhibitory and increased phosphatidylinositol (PI) responses induced by epidermal growth factor (EGF) in A431 cell, J. Cell. Physiol. 117: 91–100 (1983).PubMedCrossRefGoogle Scholar
  21. 21.
    Macara, I.G. Activation of 45Ca2+ influx and 22Na+/H+ exchange by epidermal growth factor and vanadate in A431 cells is independent of phosphatidylinositol turnover and is inhibited by phorbol ester and diacylglycerol, J. Biol. Chem. 261: 9321–9327 (1986).PubMedGoogle Scholar
  22. 22.
    Wahl, M.I., Sweatt, J.D., Carpenter, G. Epidermal growth factor stimulates inositol triphosphate formation in cells which overexpress the EGF receptor, Biochem. Biophys. Res. Comm. 142: 688–695 (1987)Google Scholar
  23. 23.
    Taylor, D., Uhing, R.J., Blackmore, P.F., Prpic, V., Exton, J.H. Insulin and epidermal growth factor do not affect phosphoinositide metabolism in rat liver plasma membranes and hepatocytes, J. Biol. Chem. 260: 2011–2014 (1985)PubMedGoogle Scholar
  24. 24.
    Besterman, J.M., Watson, S.P., Cuatrecasas, P. Lack of association of epidermal growth factor-, insulin-, and serum-induced mitogenesis ‘ with stimulation of phosphoinositide degradation in Balb/c 3T3 fibroblasts, J. Biol. Chem. 261: 723–727 (1986)PubMedGoogle Scholar
  25. 25.
    Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters, J. Biol. Chem. 257: 7847–7851 (1982).Google Scholar
  26. 26.
    Yamanishi, J., Takai, Y., Kaibuchi, K., Sano, K., Castagna, M., and Nishizuka, Y. Synergistic functions of phorbol ester and calcium in serotonin release from human platelets,’ Biochem. Biophys. Res. Commun. 112: 778–786 (1983).Google Scholar
  27. 27.
    Niedel, J.E., Kuhn, L.J., and Vandenbark, G.R. Phorbol diester receptor copurifies with protein kinase C, Proc. Natl. Acad. Sci. U.S.A. 80: 36–40 (1983).CrossRefGoogle Scholar
  28. 28.
    Nishizuka, Y. Studies and perspectives of protein kinase C, Science 233: 305–312 (1986).PubMedCrossRefGoogle Scholar
  29. 29.
    Shoyab, M., DeLarco, J.E., and Todaro, G.J. Biologically active phorbol esters specifically alter affinity of epidermal growth factor membrane receptors, Nature 279: 387–391 (1979).PubMedCrossRefGoogle Scholar
  30. 30.
    Davis, R.J., and Czech, M.P. Tumor-promoting phorbol diesters mediate phosphorylation of the epidermal growth factor receptor, J. Biol. Chem. 259: 8545–8549 (1984).Google Scholar
  31. 31.
    Friedman, B., Frackelton, Jr., A.R., Ross, A.H., Connors, J.M., Fujiki, H., Sugimura, T., and Rosner, M.R. Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor, Proc. Natl. Acad. Sci. U.S.A. 81: 3034–3038 (1984).CrossRefGoogle Scholar
  32. 32.
    Cochet, C., Gill, G.N., Meisenhelder, J., Cooper, J.A., and Hunter, T. C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity, J. Biol. Chem. 259: 2553–2558 (1984).PubMedGoogle Scholar
  33. 33.
    Downward, J., Waterfield, M.D., and Parker, P.J. Autophosphorylation and protein kinase C phosphorylation of the epidermal growth factor receptor, J. Biol. Chem. 260: 14538–14546 (1985).PubMedGoogle Scholar
  34. 34.
    Lee, L.S., and Weinstein, I.B. Tumor-promoting phorbol esters inhibit binding of epidermal growth factor to cellular receptors, Science 202: 313–315 (1978).PubMedCrossRefGoogle Scholar
  35. 35.
    Salomon, D.S. Inhibition of epidermal growth factor binding to mouse embryonal carcinoma cells by phorbol esters mediated by specific phorbol ester receptors, J. Biol. Chem. 256: 7958–7966 (1981).PubMedGoogle Scholar
  36. 36.
    King, A.C., and Cuatrecasas, P. Resolution of high and low affinity epidermal growth factor receptors, J. Biol. Chem. 257: 3053–3060 (1982).PubMedGoogle Scholar
  37. 37.
    Beguinot, L., Hanover, J.A., Ito, S., Richert, N.D., Willingham, M.C., and Pastan, I. Phorbol esters induce transient internalization without degradation of unoccupied epidermal growth factor receptors, Proc. Natl. Acad. Sci. U.S.A. 82: 2774–2778 (1985).CrossRefGoogle Scholar
  38. 38.
    Davis, R.J., and Czech, M.P. Tumor-promoting phorbol diesters cause the phosphorylation of epidermal growth factor receptors in normal human fibroblasts at threonine-654, Proc. Natl. Acad. Sci. U.S.A. 82: 1974–1978 (1985).CrossRefGoogle Scholar
  39. 39.
    Hunter, T., Ling, N., Cooper, J.A. 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).PubMedCrossRefGoogle Scholar
  40. 40.
    Phillips, M.A., and Jaken, S. Specific desensitization to tumor-promoting phorbol esters in mouse pituitary cells, J. Biol. Chem. 258: 2875–2881 (1983).Google Scholar
  41. 41.
    Collins, M.K.L., and Rozengurt, E. Homologous and heterologous mitogenic desensitization of Swiss 3T3 cells to phorbol esters and vasopressin: Role of receptor and postreceptor steps, J. Cell. Physiol. 118: 133–142 (1984).PubMedCrossRefGoogle Scholar
  42. 42.
    Rodriguez-Pena, A., and Rozengurt, E. Disappearance of Ca2+ - sensitive, phospholipid-dependent protein kinase activity in phorbol ester-treated 3T3 cells, Biochem. Biophys. Res. Commun. 120: 1053–1059 (1984).Google Scholar
  43. 43.
    Lee, L.S., and Weinstein, I.B. Mechanism of tumor promoter inhibition of cellular binding of epidermal growth factor, Proc. Natl. Acad. Sci. U.S.A. 76: 5168–5172 (1979).CrossRefGoogle Scholar
  44. 44.
    Collins, M.K.L., and Rozengurt, E. Binding of phorbol esters to high-affinity sites on murine fibroblastic cells elicits a mitogenic response, J. Cell. Physiol. 112: 42–50 (1982).CrossRefGoogle Scholar
  45. 45.
    Vara, F., and Rozengurt, E. Stimulation of Na+/H+ antiport activity by epidermal growth factor and insulin occurs without activation of protein kinase C, Biochem. Biophys. Res. Commun. 130: 646–653 (1985).Google Scholar
  46. 46.
    Grinstein, S., Mack, E., and Mills, G.B. Osmotic activation of the Na /H antiport in protein kinase C-depleted lymphocytes, Biochem. Biophys. Res. Commun. 134: 8–13 (1986).Google Scholar
  47. 47.
    Korneluk, R.G., Mahuran, D.J., Neote, K., Klavins, M.H., O’Dowd, B.F., Tropak, M., Willard, H.F., Anderson, M-J., Lowden, J.A., Gravel, R.A. Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase: extensive homology between the alpha-and beta-subunits and studies of Tay-Sachs disease, J. Biol. Chem. 261: 8407–8413 (1986)PubMedGoogle Scholar
  48. 48.
    Krupp, M.N., Connolly, D.T., and Lane, M.D. Synthesis, turnover, and down-regulation of epidermal growth factor receptors in human A431 epidermoid carcinoma cells and skin fibroblasts, J. Biol. Chem. 257: 11489–11496 (1982).PubMedGoogle Scholar
  49. 49.
    Filmus, J., Pollak, M.N., Cailleau, R., and Buick, R.N. MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited by EGF, Biochem. Biophys. Res. Commun. 128: 898–905 (1985).Google Scholar
  50. 50.
    Davis, R.J., and Czech, M.P. Platelet-derived growth factor mimics phorbol diester action on epidermal growth factor receptor phosphorylation at threonine-654, Proc. Natl. Acad. Sci. U.S.A. 82: 4080–4084 (1985).CrossRefGoogle Scholar
  51. 51.
    Fearon, C.W., and Tashjian, Jr., A.H. Thyrotropin-releasing hormone induces redistribution of protein kinase C in GH4C1 rat pituitary cells, J. Biol. Chem. 260: 8366–8371 (1985).Google Scholar
  52. 52.
    Thomas, A.P., Marks, J.S., Coll, K.E., and Williamson, J.R. Quantitation and early kinetics of inositol lipid changes induced by vasopressin in isolated and cultured hepatocytes, J. Biol. Chem. 258: 5716–5725 (1983).PubMedGoogle Scholar
  53. 53.
    Pledger, W.J., Hart, C.A., and Wharton, W.R. Mammalian cell proliferation is regulated by the synergisitic actions of multiple growth factors, Adv. Exp. Med. Biol. 138: 287–300 (1982).Google Scholar
  54. 54.
    Rozengurt, E. Growth factors, cell proliferation and cancer: An overview, Mol. Biol. Med. 1: 169–181 (1983).Google Scholar
  55. 55.
    Assoian, R.K. Biphasic effects of type p transforming growth factor on epidermal growth factor receptors in NRK fibroblasts, J. Biol. Chem. 260: 9613–9617 (1985).PubMedGoogle Scholar
  56. 56.
    DeLarco, J.E., Todaro, G.J., Growth factors from murine sarcoma virus-transformed cells. Proc. Natl. Acad. Sci. U.S.A. 75: 4001–4005 (1978)CrossRefGoogle Scholar
  57. 57.
    Todaro, G.J., Fryling, C., DeLarco, J.E., Transforming growth factors produced by certain human tumor cells: polypeptides that interact with epidermal growth factor receptors. Proc. Natl. Acad. Sci. U.S.A. 77: 5258–5262 (1980)PubMedCrossRefGoogle Scholar
  58. 58.
    Massague, J., Epidermal growth factor-like transforming growth factor I. isolation, chemical characterization, and potentiation by other transforming factors from feline sarcoma virus-transformed rat cells. J. Biol. Chem. 258: 13606–13613 (1983)Google Scholar
  59. 59.
    Marquardt, H., Hunkapiller, M.W., Hood, L.E., Twardzik, D.R., DeLarco, J.E., Stephenson, J.R., Todaro, G.J., Transforming growth factors produced by retrovirus-transformed rodent fibroblasts and human melanoma cells: amino acid sequence homology with epidermal growth factor. Proc. Natl. Acad. Sci. U.S.A. 80: 4684–4688 (1983)PubMedCrossRefGoogle Scholar
  60. 60.
    Derynck R., Roberts A.B., Winkler M.E., Chen E.Y., Goeddel D.V., Human transforming growth factor- G:: precursor structure and expression in E. coli. Cell 38: 287 (1984)Google Scholar
  61. 61.
    Lee D.C., Rose T.M., Webb N.R., Todaro G.J. Cloning and sequence analysis of a cDNA for rat transforming growth factor-cx. Nature 313: 489–492 (1985)PubMedCrossRefGoogle Scholar
  62. 62.
    Massague, J., Epidermal growth factor-like transforming growth factor II. J. Biol. Chem. 258: 13614–13620 (1983)PubMedGoogle Scholar
  63. 63.
    Carpenter, G., Stoschek, C.M., Preston, Y.A., DeLarco, J.E., Antibodies to the epidermal growth factor receptor block the biological activities of sarcoma growth factor. Proc. Natl. Acad. Sci. U.S.A. 80: 5627–5630 (1983)PubMedCrossRefGoogle Scholar
  64. 64.
    Samsoondar, J, Kobrin, M.S., Kudlow, J.E. Alpha-transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture: I. Purification from conditioned medium, J. Biol. Chem. 261: 14408–14413 (1986)Google Scholar
  65. 65.
    Kudlow, J.E., Gerrie, B.M., Production of growth factor activity by cultured bovine calf anterior pituitary cells. Endocrinology 113: 104–112 (1983)PubMedCrossRefGoogle Scholar
  66. 66.
    Kudlow, J.E., Kobrin, M.S., Secretion of epidermal growth factor-like mitogens by cultured cells from bovine anterior pituitary glands. Endocrinology 115: 911–921 (1984)PubMedCrossRefGoogle Scholar
  67. 67.
    Samsoondar, J., Kudlow, J.E., Partial purification of an adrenal growth factor produced by normal bovine anterior pituitary cells in culture. Endocrinology 120: 929–935 (1987)PubMedCrossRefGoogle Scholar
  68. 68.
    Kobrin M.S., Samsoondar J., Kudlow J.E. Alpha-Transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. II. Identification using a sequence-specific monoclonal antibody. J Biol Chem 261: 14414 (1986)PubMedGoogle Scholar
  69. 69.
    Kobrin, M.S., Asa, S.L., Samsoondar, J., Kudlow, J.E. Alpha-transforming growth factor in the bovine anterior pituitary gland: secretion by dispersed cells and immunohistochemical localization. Endocrinology 121: 1412–1416 (1987)PubMedCrossRefGoogle Scholar
  70. 70.
    Chabot J-G., Walker P., Pelletier G. Distribution of epidermal growth factor binding sites in the adult rat anterior pituitary gland. Peptides 7: 45–50 (1986)PubMedCrossRefGoogle Scholar
  71. 71.
    Asa S.L., Kovacs K., Tindall G.T., Barrow D.L., Horvath E., Vecsei P. Cushing’s disease associated with an intracellar gangliocytoma producing corticotropin-releasing factor. Ann. Internal Med. 101: 789 – 793 (1984)CrossRefGoogle Scholar
  72. 72.
    Asa S.L., Scheithauer B.W., Bilbao J.M., Horvath E., Ryan N., Kovacs K., Randall R.V., Laws E.R., Singer W., Linfoot J.A., Thorner M.O., Vale W.W. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytoma producing growth hormone-releasing factor. J. Clin. Endocrinol. Metab. 58: 796–803 (1984)PubMedCrossRefGoogle Scholar
  73. 73.
    Scheithauer B.W., Kovacs K., Randall R.V., Ryan N. Pituitary gland in hypothyroidism. Histologic and immunocytologic study. Arch. Pathol. Lab. Med. 109: 499–507 (1985)Google Scholar
  74. 74.
    Asa S.C., Penz G., Kovacs K., Ezrin C. Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis. Arch. Pathol. Lab. Med. 106: 360–369 (1982)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Jeffrey E. Kudlow
    • 1
  • Jeffrey D. Bjorge
    • 1
  • Michael S. Kobrin
    • 1
  • Andrew J. Paterson
    • 1
  1. 1.Departments of Clinical Biochemistry and Medicine Banting and Best Diabetes CentreUniversity of TorontoTorontoCanada

Personalised recommendations