Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents

EMBO J. 1996 Oct 1;15(19):5314-25.

Abstract

Several non-physiologic agents such as radiation, oxidants and alkylating agents induce ligand-independent activation of numerous receptor tyrosine kinases (RTKs) and of protein tyrosine kinases at the inner side of the plasma membrane (e.g. Dévary et al., 1992; Sachsenmaier et al., 1994; Schieven et al., 1994; Coffer et al., 1995). Here we show additional evidence for the activation of epidermal growth factor receptor (EGFR), and we show activation of v-ErbB, ErbB2 and platelet-derived growth factor receptor. As a common principle of action the inducing agents such as UVC, UVB, UVA, hydrogen peroxide and iodoacetamide inhibit receptor tyrosine dephosphorylation in a thiol-sensitive and, with the exception of the SH-alkylating agent, reversible manner. EGFR dephosphorylation can also be modulated by these non-physiologic agents in isolated plasma membranes in the presence of Triton X-100. Further, substrate (EGFR) and phosphatase have been separated: a membrane preparation of cells that have been treated with epidermal growth factor (EGF) and whose dephosphorylating enzymes have been permanently destroyed by iodoacetamide can be mixed with a membrane preparation from untreated cells which re-establishes EGFR dephosphorylation. This dephosphorylation can be modulated in vitro by UV and thiol agents. We conclude that RTKs exhibit significant spontaneous protein kinase activity; several adverse agents target (an) essential SH-group(s) carried by (a) membrane-bound protein tyrosine phosphatase(s).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Alkylating Agents / pharmacology
  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Iodoacetamide / pharmacology
  • Manganese Compounds / pharmacology
  • Oncogene Proteins v-erbB / metabolism
  • Oxidants / pharmacology
  • Oxides / pharmacology
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / physiology
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Growth Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Ultraviolet Rays*
  • Vanadates / pharmacology

Substances

  • Alkylating Agents
  • Enzyme Inhibitors
  • Manganese Compounds
  • Oncogene Proteins v-erbB
  • Oxidants
  • Oxides
  • Receptors, Growth Factor
  • permanganic acid
  • Vanadates
  • Hydrogen Peroxide
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatases
  • Acetylcysteine
  • Iodoacetamide