Linked Life Data

16246327

Source:http://linkedlifedata.com/resource/pubmed/id/16246327

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2005-11-21
pubmed:abstractText
Evolutionarily conserved sequences of the E3/protein-ubiquitin ligase Cbl regulate epidermal growth factor receptor (EGF-R) signaling and degradation. These sequences encompass Cbl's tyrosine kinase-binding domain, linker region, RING finger (RF), and an uncharacterized flank C-terminal to the RF (residues 420-436). The latter domain, designated the RF tail, extends beyond Cbl's ubiquitin-conjugating enzyme (Ubc)-binding domain and has no known function. We report structure-function studies evaluating the impact of Cbl RF tail truncations on EGF-R fate in HEK 293 cells. All of the truncation mutants exhibit greatly reduced binding to activated EGF-R and lack proline-rich sequences that mediate direct Cbl association with SH3 proteins such as Grb2, yet a subset of mutants collectively enhances EGF-R ubiquitination, downregulation, and degradation. Significantly, EGF-R degradation correlates better with RF tail-dependent degradation of the Cbl substrate Sprouty2 than with EGF-R ubiquitination: expression of the RF tail truncation mutant Cbl 1-433 enhanced EGF-R ubiquitination while impeding Sprouty2 degradation, and Cbl 1-433 failed to enhance EGF-R downregulation or degradation. Our results suggest that EGF-R fate is controlled by a checkpoint downstream of receptor ubiquitination whose regulation by the Cbl RF tail may require Sprouty2 degradation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0014-4827
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
311
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
281-93
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16246327-Amino Acid Sequence, pubmed-meshheading:16246327-Cells, Cultured, pubmed-meshheading:16246327-Conserved Sequence, pubmed-meshheading:16246327-Down-Regulation, pubmed-meshheading:16246327-Evolution, Molecular, pubmed-meshheading:16246327-Humans, pubmed-meshheading:16246327-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:16246327-Molecular Sequence Data, pubmed-meshheading:16246327-Mutation, pubmed-meshheading:16246327-Phosphorylation, pubmed-meshheading:16246327-Protein Structure, Tertiary, pubmed-meshheading:16246327-Proteins, pubmed-meshheading:16246327-Proto-Oncogene Proteins c-cbl, pubmed-meshheading:16246327-Receptor, Epidermal Growth Factor, pubmed-meshheading:16246327-Sequence Deletion, pubmed-meshheading:16246327-Tyrosine, pubmed-meshheading:16246327-Ubiquitin
pubmed:year
2005
pubmed:articleTitle
The Cbl RING finger C-terminal flank controls epidermal growth factor receptor fate downstream of receptor ubiquitination.
pubmed:affiliation
Department of Pharmacology, Carver College of Medicine, University of Iowa, 51 Newton Road 2-471 BSB, Iowa City, IA 52242, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural