Toxic Conjugates of Epidermal Growth Factor and Asialofetuin

  • Harvey R. Herschman
  • Daniel Cawley
  • David L. Simpson


Our laboratory has, for a number of years, been interested in the role and mode of action of polypeptide growth factors. These agents bind to specific cell surface receptors and initiate a cascade of biological responses leading either to cell division or expression of a new phenotype as a consequence of ligand-receptor interactions. In many cases one of the most notable initial responses is ligand-induced endocytosis of the receptor-ligand complex, with eventual degradation of the ligand and, in some cases, degradation of the receptor as well. As one of several approaches (Herschman et al., 1982) to the study of polypeptide hormone/growth factor induced responses, we have constructed heteroconjugates of binding ligands with protein toxins or their enzymic portions.


Epidermal Growth Factor Receptor Epidermal Growth Factor A431 Cell Diphtheria Toxin Hepatocyte Culture 
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. Aharonov, A., Pruss, R.M., and Herschman, H.R., 1978, Epidermal growth factor: Relationship between receptor regulation and mitogenesis in 3T3 cells, J. Biol. Chem., 253:3970.PubMedGoogle Scholar
  2. Attie, A.D., Weinstein, D.B., Freeze, H.H., Pittman, R.C. and Steinberg, D., 1979, Altered catabolism of desialylated low-density lipoprotein in the pig and in cultured rat hepatocytes, J. Biochem., 180:643.Google Scholar
  3. Butler-Gralla, E., and Herschman, H.R., 1981, Variants of 3T3 cells lacking mitogenic response to the tumor promoter tetradecanoyl-phorbol-acetate, J. Cell. Physiol., 107:59.PubMedCrossRefGoogle Scholar
  4. Carpenter, G., and Cohen, S., 1979, Epidermal growth factor, Ann. Rev. Biochem., 48:193.PubMedCrossRefGoogle Scholar
  5. Cawley, D.B., Hedblom, M.L., and Houston, L.L., 1978, Homology between ricin and Ricinus communis agglutinin: Amino terminal sequence analysis and protein synthesis inhibition studies, Arch. Biochem. Biophys., 190:744.PubMedCrossRefGoogle Scholar
  6. Cawley, D.B., Simpson, D.L., and Herschman, H.R., 1981, Asialoglycoprotein receptor mediates the toxic effects of an asialofetuin-diphtheria toxin fragment A conjugate on cultured rat hepatocytes, Proc. Natl. Acad. Sci. USA., 78:3383.PubMedCrossRefGoogle Scholar
  7. Cawley, D.B., Herschman, H.R., Gilliland, D.G., and Collier, R.J., 1980, Epidermal growth factor-toxin A chain conjugates: EGF-ricin A is a potent toxin while EGF-diphtheria fragment A is non-toxic, Cell., 22:563.PubMedCrossRefGoogle Scholar
  8. Chung, D.N., and Collier, R.J., 1977, The mechanism of ADP- ribosylation of elongation factor 2, Biochim. Biophys. Acta., 483:248.PubMedCrossRefGoogle Scholar
  9. De Lange, R.J., Williams, L.S., Drazin, R.E., and Collier, R.J., 1979. The amino acid sequence of fragment A, an enzymically active fragment of diphtheria toxin, J.Biol. Chem., 254:5838.Google Scholar
  10. Fabricant, R.N., DeLarco, J.E., and Todaro, G.J., 1977, Nerve growth factor receptors on human melanoma cells in culture., Proc. Natl. Acad. Sci. USA., 74:565.PubMedCrossRefGoogle Scholar
  11. Fine, R.E., Goldenberg, R., Sorrentino, J., and Herschman, H.R., 1981, Subcellular structures involved in internalization and degradation of epidermal growth factor, J. Supramol. Struct., 15:235.CrossRefGoogle Scholar
  12. Funatsu, G., Yoshitake, S., and Funatsu, M., 1978, Primary structure of the chain of ricin D, Agric. Biol. Chem., 42:501.CrossRefGoogle Scholar
  13. Gilliland, D.G., Steplewski, Z., Collier, R.J., Mitchell, K.F., Chang, T.H., and Korprowski, H., 1980, Antibody-directed cytotoxic agents: Use of monoclonal antibody to direct the action of toxin A chains to colorectal carcinoma cells, Proc. Natl. Acad. Sci. USA., 77:4539.PubMedCrossRefGoogle Scholar
  14. Herschman, H.R., Sorrentino, J., Butler-Gralla, E., and Cawley, D., 1982, Isolation and characterization of variants of 3T3 cells deficient in a proliferative response to specific mitogens in: “Maturation Factors and Cancer,” M. Moore, ed., Raven Press, New York.Google Scholar
  15. Honjo, T., Nishizuka, Y., Hayaishi, D., and Kato, I., 1968, Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl-transferase II and inhibition of protein synthesis, J. Biol. Chem., 243:3553.PubMedGoogle Scholar
  16. Houston, L.L., 1982, Transport of ricin A chain after prior treatment of mouse leukemia cells with ricin B chain, J. Biol. Chem., 257:1532.PubMedGoogle Scholar
  17. Hubbard, A.L., Wilson, G., Ashwell, G., and Stuckenbrok, H., 1979, An electron microscope autoradiographic study of the carbohydrate recognition systems in rat liver. I. Distribution of iodine-125 labeled ligands among the liver cell types, J. Cell Biol., 83:47.PubMedCrossRefGoogle Scholar
  18. Kawasaki, T., and Ashwell, G., 1976, Chemical and physical properties of a hepatic membrane protein that specifically binds asialoglycoproteins, J. Biol. Chem., 251:1296.PubMedGoogle Scholar
  19. Moehring, T.J. and Moehring, J.M., 1977, Selection and characterization of cells resistant to diphtheria toxin and Pseudomonas exotoxin A: Presumptive translational mutants, Cell., 11:447.PubMedCrossRefGoogle Scholar
  20. Olsnes, S., and Pihl, A., 1982a, Toxic lectins and related proteins in “The Molecular Actions on Toxins and Viruses,” Van Heyningen, S., and Cohen, P., eds., Elsevier/North Holland, Amsterdam.Google Scholar
  21. Olsnes, S., and Pihl, A., 1982b, Chimeric Toxins, Pharmac. Ther., 15:335.Google Scholar
  22. Pruss, R.M., and Herschman, H.R., 1977, Variants of 3T3 cells lacking mitogenic response to epidermal growth factor, Proc. Natl. Acad. Sci. USA 74: 3918.PubMedCrossRefGoogle Scholar
  23. Rose, S.P., Pruss, R.M., and Herschman, H.R., 1975, Initiation of 3T3 fibroblast cell division by epidermal growth factor, J. Cell. Physiol. 86:593.PubMedCrossRefGoogle Scholar
  24. Sandvig, K., Olsnes, S., and Pihl, A., 1976, Kinetics of the binding of the toxic lectins abrin and ricin to surface receptors of human cells, J. Biol. Chem. 251:3977.PubMedGoogle Scholar
  25. Simpson, D.L., Cawley, D.B., and Herschman, H.R., 1982, Killing of cultured hepatocytes by conjugates of asialof etuin and EGF linked to the A-chain of ricin or diptheria toxin, Cell 29:469.PubMedCrossRefGoogle Scholar
  26. Steer, C.J., and Ashwell, G., 1980, Studies on a mammalian hepatic binding protein specific for asialoglycoproteins, J. Biol. Chem. 255:3008.PubMedGoogle Scholar
  27. Uchida, T., Mekada, E., and Okada, Y., 1980, Hybrid toxin of the A chain of ricin toxin and a subunit of Wisteria Floribunda lectin, J. Biol. Chem. 255:6687.PubMedGoogle Scholar
  28. Youle, R.J., Murray, G.J., and Neville, D.M. Jr., 1979, Ricin linked to monophosphopentamannose binds to fibroblast lysosomal hydrolase receptors, resulting in a cell-type specific toxin, Proc. Natl. Acad. Sci. USA 76:5559.PubMedCrossRefGoogle Scholar
  29. Youle, R.J., Murray, G.J., and Neville, D.M., Jr., 1981, Studies on the galactose-binding site of ricin and the hybrid toxin man-6P-ricin, Cell 23:551.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Harvey R. Herschman
    • 1
  • Daniel Cawley
    • 1
  • David L. Simpson
    • 1
  1. 1.Department of Biological Chemistry, and Laboratory of Biomedical and Environmental SciencesUCLA Center for the Health SciencesLos AngelesUSA

Personalised recommendations