Toxic ligand conjugates as tools in the study of receptor‐ligand interactions

Harvey R. Herschman, David L. Simpson, Daniel B. Cawley

Research output: Contribution to journalReview article

11 Scopus citations

Abstract

We have constructed hybrid proteins in which the toxic A chains of ricin or diptheria toxin have been linked to either asialofetuin, fetuin, or epidermal growth factor (EGF). Both ASF‐RTA and ASF‐DTA are potent toxins on cultured rat hepatocytes, cells that display the asialoglycoprotein receptor. Toxicity of these two compounds is restricted to hepatocytes and can be blocked by asialoglycoproteins but not the native glycoproteins or asialoagalactoglycoprotein derivatives, indicating that the toxicity of the conjugates is mediated by the hepatic asialoglycoprotein receptor. The EGF‐RTA conjugate is an extremely potent toxin on cells that can bind the hormone, but is only poorly effective on cells that are unable to bind EGF. The EGF‐DTA conjugate, in contrast, is unable to kill 3T3 cells and is at least two orders of magnitude less effective than EGF‐RTA on A431 cells, a cell line with 1‐2 × 106 EGF receptors per cell. However, when EGF‐RTA and EGF‐DTA were tested on primary liver hepatocyte cultures, which were susceptible to both ASF‐RTA and ASF‐DTA, both EGF conjugates were potent toxins. Sensitivity of the hepatocyte cultures to ricin toxicity increases slightly during a 52‐hr culture period. In contrast, sensitivity to EGF‐RTA and ASF‐RTA decline dramatically during this period. Receptors for both ligands remain plentiful on the cell surface during this time.

Original languageEnglish (US)
Pages (from-to)163-176
Number of pages14
JournalJournal of cellular biochemistry
Volume20
Issue number2
DOIs
StatePublished - 1982

Keywords

  • asialoglycoprotein receptor
  • chimeric toxins
  • diphtheria toxin
  • epidermal growth factor
  • hybrid toxins
  • ricin
  • toxic conjugates

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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