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Chem Biol. 2007 Jul;14(7):764-74.

Regulation of c-Src nonreceptor tyrosine kinase activity by bengamide A through inhibition of methionine aminopeptidases.

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1
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 N. Wolfe Street Baltimore, MD 21205, USA.

Abstract

Methionine aminopeptidases (MetAPs) remove the N-terminal initiator methionine during protein synthesis, a prerequisite step for N-terminal myristoylation. N-myristoylation of proto-oncogene c-Src is essential for its membrane association and proper signal transduction. We used bengamides, a family of general MetAP inhibitors, to understand the downstream physiological functions of MetAPs. c-Src from bengamide A-treated cells retained its N-terminal methionine and suffered a decrease in N-terminal myristoylation, which was accompanied by a shift of its subcellular distribution from the plasma membrane to the cytosol. Furthermore, bengamide A decreased the tyrosine kinase activities of c-Src both in vitro and in vivo and eventually delayed cell-cycle progression through G(2)/M. Thus, c-Src is a physiologically relevant substrate for MetAPs whose dysfunction is likely to account for the cell-cycle effects of MetAP inhibitors including bengamide A.

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PMID:
17656313
PMCID:
PMC3165037
DOI:
10.1016/j.chembiol.2007.05.010
[Indexed for MEDLINE]
Free PMC Article

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