Document Detail


SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron.
MedLine Citation:
PMID:  23154983     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The conserved E3 ubiquitin ligase component named SEL-10 in Caenorhabditis elegans and Fbw7 in mammals targets substrates for ubiquitin-mediated degradation through a high-affinity binding site called a Cdc4 phosphodegron (CPD). As many known substrates of Fbw7 are oncoproteins, the identification of new substrates may offer insight into cancer biology as well as aspects of proteome regulation. Here, we evaluated whether the presence of an evolutionarily conserved CPD would be a feasible complement to proteomics-based approaches for identifying new potential substrates. For functional assessments, we focused on LIN-45, a component of the signal transduction pathway underlying vulval induction and the ortholog of human Braf, an effector of Ras in numerous cancers. Our analysis demonstrates that LIN-45 behaves as a bona fide substrate of SEL-10, with mutation of the CPD or loss of sel-10 resulting in increased activity and protein stability in vivo. Furthermore, during vulval induction, the downstream kinase MPK-1/ERK is also required for LIN-45 protein degradation in a negative feedback loop, resulting in degradation of LIN-45 where ERK is highly active. As the CPD consensus sequence is conserved in human Braf, we propose that Fbw7 may also regulate Braf stability in some cell contexts. We discuss the implications of our findings for vulval development in C. elegans, the potential applicability to human Braf, and the value of a CPD-based predictive approach for human Fbw7 substrates.
Authors:
Claire de la Cova; Iva Greenwald
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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:  Genes & development     Volume:  26     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-16     Completed Date:  2013-01-17     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2524-35     Citation Subset:  IM    
Affiliation:
Howard Hughes Medical Institute.
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MeSH Terms
Descriptor/Qualifier:
Animals
Caenorhabditis elegans / genetics,  metabolism,  physiology*
Caenorhabditis elegans Proteins / genetics,  metabolism*
Cell Cycle Proteins / genetics,  metabolism*
Down-Regulation
Feedback, Physiological*
Humans
Protein Binding
Proto-Oncogene Proteins B-raf / genetics,  metabolism*
Signal Transduction / genetics*
Ubiquitin-Protein Ligases / genetics,  metabolism
Vertebrates / genetics
raf Kinases / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
P40 OD010440/OD/NIH HHS; R01 CA095389/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Caenorhabditis elegans Proteins; 0/Cell Cycle Proteins; 0/SEL-10 protein, C elegans; EC 2.7.1.-/lin-45 protein, C elegans; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 2.7.11.1/raf Kinases; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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