Regulation of c-Src nonreceptor tyrosine kinase activity by bengamide A through inhibition of methionine aminopeptidases.
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.
Hu
Xiaoyi
X
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 N. Wolfe Street Baltimore, MD 21205, USA.
Dang
Yongjun
Y
Tenney
Karen
K
Crews
Phillip
P
Tsai
Chiawei W
CW
Sixt
Katherine M
KM
Cole
Philip A
PA
Liu
Jun O
JO
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*
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