INHIBITION OF PROTEIN-KINASE-C BY THE TYROSINE KINASE INHIBITOR ERBSTATIN

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. © 1990.