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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2003-3-25
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pubmed:abstractText |
The c-Abl tyrosine kinase is inhibited by mechanisms that are poorly understood. Disruption of these mechanisms in the Bcr-Abl oncoprotein leads to several forms of human leukemia. We found that like Src kinases, c-Abl 1b is activated by phosphotyrosine ligands. Ligand-activated c-Abl is particularly sensitive to the anti-cancer drug STI-571/Gleevec/imatinib (STI-571). The SH2 domain-phosphorylated tail interaction in Src kinases is functionally replaced in c-Abl by an intramolecular engagement of the N-terminal myristoyl modification with the kinase domain. Functional studies coupled with structural analysis define a myristoyl/phosphotyrosine switch in c-Abl that regulates docking and accessibility of the SH2 domain. This mechanism offers an explanation for the observed cellular activation of c-Abl by tyrosine-phosphorylated proteins, the intracellular mobility of c-Abl, and it provides new insights into the mechanism of action of STI-571.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0092-8674
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
112
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
845-57
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12654250-Animals,
pubmed-meshheading:12654250-Catalysis,
pubmed-meshheading:12654250-Cell Line,
pubmed-meshheading:12654250-Cercopithecus aethiops,
pubmed-meshheading:12654250-Enzyme Inhibitors,
pubmed-meshheading:12654250-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:12654250-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:12654250-Humans,
pubmed-meshheading:12654250-Ligands,
pubmed-meshheading:12654250-Models, Biological,
pubmed-meshheading:12654250-Models, Molecular,
pubmed-meshheading:12654250-Mutation,
pubmed-meshheading:12654250-Phosphorylation,
pubmed-meshheading:12654250-Phosphotyrosine,
pubmed-meshheading:12654250-Piperazines,
pubmed-meshheading:12654250-Protein Binding,
pubmed-meshheading:12654250-Protein-Tyrosine Kinases,
pubmed-meshheading:12654250-Proto-Oncogene Proteins c-abl,
pubmed-meshheading:12654250-Pyrimidines,
pubmed-meshheading:12654250-Vero Cells,
pubmed-meshheading:12654250-src Homology Domains
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pubmed:year |
2003
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pubmed:articleTitle |
A myristoyl/phosphotyrosine switch regulates c-Abl.
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pubmed:affiliation |
Developmental Biology Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
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