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rdf:type |
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lifeskim:mentions |
umls-concept:C0031715,
umls-concept:C0033684,
umls-concept:C0139030,
umls-concept:C0752313,
umls-concept:C0812215,
umls-concept:C1145667,
umls-concept:C1171350,
umls-concept:C1706586,
umls-concept:C1826565,
umls-concept:C1879547,
umls-concept:C2746015
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pubmed:issue |
5
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pubmed:dateCreated |
2008-3-7
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pubmed:abstractText |
The Raf-MEK-ERK pathway regulates many fundamental biological processes, and its activity is finely tuned at multiple levels. The Raf kinase inhibitory protein (RKIP) is a widely expressed negative modulator of the Raf-MEK-ERK signaling pathway. We have previously shown that RKIP inhibits the phosphorylation of MEK by Raf-1 through interfering with the formation of a kinase-substrate complex by direct binding to both Raf-1 and MEK. Here, we show that the evolutionarily conserved ligand-binding pocket of RKIP is required for its inhibitory activity towards the Raf-1 kinase mediated activation of MEK. Single amino acid substitutions of two of the conserved residues form the base and the wall of the pocket confers a loss-of-function phenotype on RKIP. Loss-of-function RKIP mutants still appear to bind to Raf-1. However the stability of the complexes formed between mutants and the N-region Raf-1 phosphopeptide were drastically reduced. Our results therefore suggest that the RKIP conserved pocket may constitute a novel phosphoamino-acid binding motif and is absolutely required for RKIP function.
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pubmed:grant |
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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 |
May
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pubmed:issn |
0898-6568
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
20
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
935-41
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pubmed:dateRevised |
2011-9-22
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pubmed:meshHeading |
pubmed-meshheading:18294816-Amino Acid Substitution,
pubmed-meshheading:18294816-Animals,
pubmed-meshheading:18294816-Binding Sites,
pubmed-meshheading:18294816-COS Cells,
pubmed-meshheading:18294816-Cercopithecus aethiops,
pubmed-meshheading:18294816-Conserved Sequence,
pubmed-meshheading:18294816-Humans,
pubmed-meshheading:18294816-MAP Kinase Signaling System,
pubmed-meshheading:18294816-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:18294816-Models, Molecular,
pubmed-meshheading:18294816-Mutagenesis, Site-Directed,
pubmed-meshheading:18294816-Phosphatidylethanolamine Binding Protein,
pubmed-meshheading:18294816-Phosphorylation,
pubmed-meshheading:18294816-Protein Conformation,
pubmed-meshheading:18294816-Proto-Oncogene Proteins c-raf,
pubmed-meshheading:18294816-Recombinant Proteins,
pubmed-meshheading:18294816-Signal Transduction
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pubmed:year |
2008
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pubmed:articleTitle |
The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK.
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pubmed:affiliation |
The Beatson institute for Cancer Research, Cancer Research UK Garscube Estate, Bearsden, Glasgow G61 1BD, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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