Linked Life Data

15117950

Source:http://linkedlifedata.com/resource/pubmed/id/15117950

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2004-6-28
pubmed:abstractText
c-Cbl down-regulates receptor tyrosine kinases by conjugating ubiquitin to them, leading to receptor internalization and degradation. The ubiquitin protein ligase activity of c-Cbl (abbreviated as E3 activity) is mediated by its RING finger domain. We show here that the E3 activity of c-Cbl is negatively regulated by other domains present in the amino-terminal half of the protein (the TKB and linker helix domains) and that this negative regulation is removed when the protein is phosphorylated on tyrosine residues. Protease digestion studies indicate that tyrosine phosphorylation alters the conformation of c-Cbl. We also show that mutation of certain conserved tyrosine residues to glutamate can constitutively activate the E3 activity of c-Cbl. In particular, a Y371E mutant shows constitutive E3 activity while retaining the ability to bind epidermal growth factor receptor (EGFR). The Y371E mutant also has altered protease sensitivity from wild type, instead resembling the proteolytic pattern seen with tyrosine-phosphorylated c-Cbl. Mutation of the homologous tyrosine residue in Cbl-b to glutamate also leads to E3 activation while retaining EGFR-binding ability. These studies argue that Tyr-371 plays a key role in activating the E3 activity of c-Cbl and that the Y371E mutant may partially mimic phosphorylation at that site. However, Tyr-371 point mutants of c-Cbl are still able to undergo phosphorylation-induced E3 activation, and we show that Tyr-368 can also be phosphorylated in addition to Tyr-371, and contributes to activation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
2
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
28017-27
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15117950-Cell Line, pubmed-meshheading:15117950-Down-Regulation, pubmed-meshheading:15117950-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:15117950-Gene Expression Regulation, Enzymologic, pubmed-meshheading:15117950-Glutamic Acid, pubmed-meshheading:15117950-Glutathione Transferase, pubmed-meshheading:15117950-Humans, pubmed-meshheading:15117950-Mutation, pubmed-meshheading:15117950-Phenylalanine, pubmed-meshheading:15117950-Phosphorylation, pubmed-meshheading:15117950-Point Mutation, pubmed-meshheading:15117950-Protein Binding, pubmed-meshheading:15117950-Protein Conformation, pubmed-meshheading:15117950-Protein Structure, Tertiary, pubmed-meshheading:15117950-Proto-Oncogene Proteins, pubmed-meshheading:15117950-Proto-Oncogene Proteins c-cbl, pubmed-meshheading:15117950-Receptor, Epidermal Growth Factor, pubmed-meshheading:15117950-Tyrosine, pubmed-meshheading:15117950-Ubiquitin-Protein Ligases
pubmed:year
2004
pubmed:articleTitle
Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations.
pubmed:affiliation
Department of Pathology, University of Colorado Health Sciences Center, 4200 E Ninth Avenue, Denver, CO 80262, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.