Document Detail


Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation.
MedLine Citation:
PMID:  16525057     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.
Authors:
Brian A Pierchala; Jeffrey Milbrandt; Eugene M Johnson
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  26     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-09     Completed Date:  2006-04-13     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2777-87     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA. bap7@buffalo.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Blotting, Western / methods
Cell Survival
Cells, Cultured
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Activation / drug effects
Ganglia, Sympathetic / cytology
Glial Cell Line-Derived Neurotrophic Factor / metabolism*
Immunoprecipitation / methods
Membrane Microdomains / metabolism*
Membrane Proteins / metabolism
Nerve Growth Factor / pharmacology
Neurons / cytology*,  drug effects,  metabolism
Oligopeptides / pharmacology
Proteasome Endopeptidase Complex / metabolism*
Protein Transport / drug effects,  physiology
Proto-Oncogene Proteins c-ret / classification,  physiology*
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects,  physiology*
Tetrazolium Salts / diagnostic use
Thiazoles / diagnostic use
Time Factors
Ubiquitin / metabolism
Grant Support
ID/Acronym/Agency:
AG-13729/AG/NIA NIH HHS; AG-13730/AG/NIA NIH HHS; K01 NS-045221/NS/NINDS NIH HHS; R37AG-12947/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Glial Cell Line-Derived Neurotrophic Factor; 0/Membrane Proteins; 0/Oligopeptides; 0/Tetrazolium Salts; 0/Thiazoles; 0/Ubiquitin; 0/flotillins; 134381-21-8/epoxomicin; 298-93-1/thiazolyl blue; 9061-61-4/Nerve Growth Factor; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/Ret protein, rat; EC 3.4.25.1/Proteasome Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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