Document Detail


Regulation of c-Src nonreceptor tyrosine kinase activity by bengamide A through inhibition of methionine aminopeptidases.
MedLine Citation:
PMID:  17656313     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Xiaoyi Hu; Yongjun Dang; Karen Tenney; Phillip Crews; Chiawei W Tsai; Katherine M Sixt; Philip A Cole; Jun O Liu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biology     Volume:  14     ISSN:  1074-5521     ISO Abbreviation:  Chem. Biol.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-27     Completed Date:  2007-12-13     Revised Date:  2011-09-26    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  764-74     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 N. Wolfe Street Baltimore, MD 21205, USA.
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MeSH Terms
Descriptor/Qualifier:
Aminopeptidases / antagonists & inhibitors*
Animals
Azepines / pharmacology*
Cell Line
Humans
Protease Inhibitors / pharmacology*
Proto-Oncogene Proteins pp60(c-src) / metabolism
Subcellular Fractions / enzymology,  metabolism
src-Family Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
CA047135/CA/NCI NIH HHS; CA052955/CA/NCI NIH HHS; CA074305/CA/NCI NIH HHS; CA1078743/CA/NCI NIH HHS; R01 CA078743-15/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Azepines; 0/Protease Inhibitors; EC 2.7.10.2/Proto-Oncogene Proteins pp60(c-src); EC 2.7.10.2/src-Family Kinases; EC 3.4.11.-/Aminopeptidases; EC 3.4.11.18/methionyl aminopeptidase
Comments/Corrections
Comment In:
Chem Biol. 2007 Jul;14(7):732-4   [PMID:  17656307 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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