title: Regulation of c-Src nonreceptor tyrosine kinase activity by bengamide A through inhibition of methionine aminopeptidases.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 N. Wolfe Street Baltimore, MD 21205, USA.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Hu
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.forename: Karen
authors.initials: K
authors.lastname: Tenney
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.forename: Chiawei W
authors.initials: CW
authors.lastname: Tsai
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Sixt
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D063208:Methionyl Aminopeptidases; D011480:Protease Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D001381:Azepines; C000715470:MAS1 protein, human; D011480:Protease Inhibitors; D000090063:Proto-Oncogene Mas; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases