Linked Life Data

15611073

Source:http://linkedlifedata.com/resource/pubmed/id/15611073

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2005-2-28
pubmed:abstractText
ErbB receptors associate in a ligand-dependent or -independent manner, and overexpression of epidermal growth factor receptor (ErbB1) or ErbB2 results in ligand-independent activation. Ligand-independent activation is poorly understood, and dimerization alone is not sufficient for activation. ErbB receptors also form higher order oligomers, but the mechanism of oligomer formation and their contribution to signaling are not known. The kinase-deficient ErbB3 as well as its extracellular domains are particularly prone to ligand-independent oligomerization, and oligomers are destabilized by binding of the ligand heregulin. In contrast, ligand binding facilitates heterodimerization with ErbB2 and is expected to stabilize an extended conformation of the ErbB3 extracellular domain (ECD) in which the dimerization interface is exposed. In the absence of ligand, ErbB3 can adopt a closed conformation that is held together by an intramolecular tether. We used a constitutively extended form of the ErbB3-ECD to analyze the conformation of the ECD in oligomers and the mechanism of oligomer disruption by heregulin. The extended conformation of the ECD forms oligomers more readily, suggesting the crystallographically defined dimer interface is one of the interfaces involved in oligomerization. Heregulin destabilizes oligomeric complexes but not dimers, which are neither stabilized nor disrupted by ligand binding, indicating a distinct second interface in oligomers of ErbB3. Cross-linking and activation studies on membrane-embedded ErbB3/ErbB2 chimeras confirm this dual effect of heregulin. Most of the ErbB3-ECD on the cell surface is apparently kept in an open conformation through oligomerization, and the resulting oligomers adopt a conformation representing a state of reduced activity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8238-47
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15611073-Animals, pubmed-meshheading:15611073-CHO Cells, pubmed-meshheading:15611073-Cell Line, pubmed-meshheading:15611073-Cricetinae, pubmed-meshheading:15611073-Cross-Linking Reagents, pubmed-meshheading:15611073-Crystallography, X-Ray, pubmed-meshheading:15611073-DNA, Complementary, pubmed-meshheading:15611073-Dimerization, pubmed-meshheading:15611073-Humans, pubmed-meshheading:15611073-Immunoprecipitation, pubmed-meshheading:15611073-Ligands, pubmed-meshheading:15611073-Models, Molecular, pubmed-meshheading:15611073-Neuregulin-1, pubmed-meshheading:15611073-Phosphorylation, pubmed-meshheading:15611073-Plasmids, pubmed-meshheading:15611073-Protein Binding, pubmed-meshheading:15611073-Protein Conformation, pubmed-meshheading:15611073-Protein Structure, Secondary, pubmed-meshheading:15611073-Protein Structure, Tertiary, pubmed-meshheading:15611073-Receptor, erbB-3, pubmed-meshheading:15611073-Sepharose, pubmed-meshheading:15611073-Signal Transduction, pubmed-meshheading:15611073-Spectrometry, Mass, Electrospray Ionization, pubmed-meshheading:15611073-Time Factors, pubmed-meshheading:15611073-Tyrosine
pubmed:year
2005
pubmed:articleTitle
Oligomers of ERBB3 have two distinct interfaces that differ in their sensitivity to disruption by heregulin.
pubmed:affiliation
Department of Medicine, Hematology-Oncology, UCLA, Los Angeles, California 90095, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't