Elsevier

Biochemical Pharmacology

Volume 40, Issue 9, 1 November 1990, Pages 2129-2135
Biochemical Pharmacology

Inhibition of protein kinase c by the tyrosine kinase inhibitor erbstatin

https://doi.org/10.1016/0006-2952(90)90245-GGet rights and content

Abstract

We examined the tyrosine kinase inhibitor erbstatin and several derivatives for their ability to inhibit serine/threonine protein kinases in vitro. Erbstatin was found to inhibit protein kinase C (PKC) with an ic50of 19.8 ± 3.2 μM. A trihydroxy derivative of erbstatin inhibited PKC with similar potency, whereas the corresponding methoxy derivatives were inactive. Inhibition by erbstatin was competitive with ATP (Ki= 11.0 ± 2.3 μM) and non-competitive with the phosphate acceptor, either histone or the synthetic peptide kemptide. Action of erbstatin at the catalytic stie of PKC was further indicated by the findings that it inhibited the catalytic fragment of PKC but did not inhibit the interaction of phorbol ester with the intact enzyme. Erbstatin had a similar potency against three PKC isozymes (α, β, and γ) examined. In addition, erbstatin was found to inhibit other serine/threonine kinases (assayed at their Km, for ATP). The greatest potency was observed versus the cyclic nucleotide-dependent kinases, while lower potency was seen versus myosin light chain kinase. These observations are discussed in terms of the structure and kinetic properties of PKC and the epidermal growth factor receptor tyrosine kinase.

References (38)

  • C House et al.

    A synthetic peptide analog of the putative substrate-binding motif activates protein kinase C

    FEBS Lett

    (1989)
  • C Erneux et al.

    The kinetics of tyrosine phosphorylation by the purified epidermal growth factor receptor kinase of A431 cells

    J Biol Chem

    (1983)
  • CR Loomis et al.

    Sangivamycin, a nucleoside analogue, is a potent inhibitor of protein kinase C

    J Biol Chem

    (1988)
  • RM Lyall et al.

    Tyrophostins inhibit epidermal growth factor (EGF)-receptor tyrosine kinase activity in living cells and EGF-stimulated cell proliferation

    J Biol Chem

    (1989)
  • T Shiraishi et al.

    Specific inhibitors of tyrosine-specific protein kinase, synthetic 4-hydroxycinnamamide derivatives

    Biochem Biophys Res Commun

    (1987)
  • H Hidaka et al.

    Pharmacology of the isoquinoline sulfonamide protein kinase C inhibitors

    Trends Pharmacol Sci

    (1987)
  • H Kase et al.

    K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases

    Biochem Biophys Res Commun

    (1987)
  • T Hunter et al.

    Protein tyrosine kinases

    Annu Rev Biochem

    (1985)
  • U Kikkawa et al.

    The protein kinase C family: Heterogeneity and its implications

    Annu Rev Biochem

    (1989)

    • Cited by (0)

    †

    To whom correspondence should be addressed: W. Robert Bishop, Ph.D., Schering-Plough Research B-9-1, 60 Orange St., Bloomfield, NJ 07003, U.S.A..

    View full text
    Copyright © 1990 Published by Elsevier Inc.