Document Detail


Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels.
MedLine Citation:
PMID:  23416883     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Upon activation, the epidermal growth factor (EGF) receptor becomes phosphorylated and triggers a vast signaling network that has profound effects on cell growth. The EGF receptor is observed to assemble into clusters after ligand binding and tyrosine kinase autophosphorylation, but the role of these assemblies in the receptor signaling pathway remains unclear. To address this question, we measured the phosphorylation of EGFR when the EGF ligand was anchored onto laterally mobile and immobile surfaces. We found that cells generated clusters of ligand-receptor complex on mobile EGF surfaces, and displayed a lower ratio of phosphorylated EGFR to EGF when compared to immobilized EGF that is unable to cluster. This result was verified by tuning the lateral assembly of ligand-receptor complexes on the surface of living cells using patterned supported lipid bilayers. Nanoscale metal lines fabricated into the supported membrane constrained lipid diffusion and EGF receptor assembly into micron and sub-micron scale corrals. Single cell analysis indicated that clustering impacts EGF receptor activation, and larger clusters (>1 μm(2)) of ligand-receptor complex generated lower EGF receptor phosphorylation per ligand than smaller assemblies (<1 μm(2)) in HCC1143 cells that were engaged to ligand-functionalized surfaces. We investigated the mechanism of EGFR clustering by treating cells with compounds that disrupt the cytoskeleton (Latrunculin B), clathrin-mediated endocytosis (Pitstop2), and inhibit EGFR activation (Gefitinib). These results help elucidate the nature of large-scale EGFR clustering, thus underscoring the general significance of receptor spatial organization in tuning biochemical function.
Authors:
D Stabley; S Retterer; S Marshall; K Salaita
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Integrative biology : quantitative biosciences from nano to macro     Volume:  5     ISSN:  1757-9708     ISO Abbreviation:  Integr Biol (Camb)     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-26     Completed Date:  2013-09-24     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  101478378     Medline TA:  Integr Biol (Camb)     Country:  England    
Other Details:
Languages:  eng     Pagination:  659-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Biocompatible Materials / chemistry*
Breast Neoplasms / metabolism*
Diffusion
Epidermal Growth Factor / chemistry*,  metabolism*
Female
Humans
Phosphorylation
Protein Binding
Receptor, Epidermal Growth Factor / metabolism*
Signal Transduction
Surface Properties
Tumor Cells, Cultured
Up-Regulation
Grant Support
ID/Acronym/Agency:
HHSN268201000043C//PHS HHS; R01 GM097399/GM/NIGMS NIH HHS; R01-GM097399-01/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Biocompatible Materials; 62229-50-9/Epidermal Growth Factor; EC 2.7.10.1/Receptor, Epidermal Growth Factor
Comments/Corrections

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