Regulation of c-Src Nonreceptor Tyrosine Kinase Activity by Bengamide A through Inhibition of Methionine Aminopeptidases

Xiaoyi Hu, Yongjun Dang, Karen Tenney, Phillip Crews, Chiawei W. Tsai, Katherine M. Sixt, Philip A. Cole, Jun O. Liu

Research output: Contribution to journalArticlepeer-review

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 G2/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.

Original languageEnglish (US)
Pages (from-to)764-774
Number of pages11
JournalChemistry and Biology
Volume14
Issue number7
DOIs
StatePublished - Jul 30 2007

Keywords

  • CHEMBIO

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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