Document Detail

The E3 ubiquitin ligase protein associated with Myc (Pam) regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling in vivo through N- and C-terminal domains.
MedLine Citation:
PMID:  22798074     Owner:  NLM     Status:  MEDLINE    
Pam and its homologs (the PHR protein family) are large E3 ubiquitin ligases that function to regulate synapse formation and growth in mammals, zebrafish, Drosophila, and Caenorhabditis elegans. Phr1-deficient mouse models (Phr1(Δ8,9) and Phr1(Magellan), with deletions in the N-terminal putative guanine exchange factor region and the C-terminal ubiquitin ligase region, respectively) exhibit axon guidance/outgrowth defects and striking defects of major axon tracts in the CNS. Our earlier studies identified Pam to be associated with tuberous sclerosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapamycin (mTOR) signaling. Here, we examine the potential involvement of the TSC/mTOR complex 1(mTORC1) signaling pathway in Phr1-deficient mouse models. We observed attenuation of mTORC1 signaling in the brains of both Phr1(Δ8,9) and Phr1(Magellan) mouse models. Our results establish that Pam regulates TSC/mTOR signaling in vitro and in vivo through two distinct domains. To further address whether Pam regulates mTORC1 through two functionally independent domains, we undertook heterozygous mutant crossing between Phr1(Δ8,9) and Phr1(Magellan) mice to generate a compound heterozygous model to determine whether these two domains can complement each other. mTORC1 signaling was not attenuated in the brains of double mutants (Phr1(Δ8,9/Mag)), confirming that Pam displays dual regulation of the mTORC1 pathway through two functional domains. Our results also suggest that although dysregulation of mTORC1 signaling may be responsible for the corpus callosum defects, other neurodevelopmental defects observed with Phr1 deficiency are independent of mTORC1 signaling. The ubiquitin ligase complex containing Pam-Fbxo45 likely targets additional synaptic and axonal proteins, which may explain the overlapping neurodevelopmental defects observed in Phr1 and Fbxo45 deficiency.
Sangyeul Han; Sun Kim; Samira Bahl; Lin Li; Clara F Burande; Nicole Smith; Marianne James; Roberta L Beauchamp; Pradeep Bhide; Aaron DiAntonio; Vijaya Ramesh
Related Documents :
15473684 - Characterization of the 70s ribosome from rhodopseudomonas palustris using an integrate...
2398054 - Cardiac fatty acid-binding proteins. isolation and characterization of the mitochondria...
16551684 - Arabidopsis thaliana proteomics: from proteome to genome.
20851094 - N-terminal sequencing by mass spectrometry through specific fluorescamine labeling of ...
12071704 - Large-scale expression and purification of high-molecular-weight glutenin subunits.
20722734 - Identification of putative two-component regulatory systems in the bovine pathogen mann...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-09-03     Completed Date:  2012-11-19     Revised Date:  2014-10-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30063-72     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Axons / metabolism*
Caenorhabditis elegans
Carrier Proteins / genetics,  metabolism*
Corpus Callosum / metabolism
F-Box Proteins / genetics,  metabolism
HEK293 Cells
Mice, Mutant Strains
Multiprotein Complexes
Nerve Tissue Proteins / genetics,  metabolism*
Protein Structure, Tertiary
Proteins / genetics,  metabolism*
Signal Transduction
Synapses / genetics,  metabolism*
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins / genetics,  metabolism
Ubiquitin-Protein Ligases / genetics,  metabolism*
Ubiquitination / physiology
Grant Support
Reg. No./Substance:
0/Carrier Proteins; 0/F-Box Proteins; 0/Fbxo45 protein, mouse; 0/Multiprotein Complexes; 0/Mycbp2 protein, mouse; 0/Nerve Tissue Proteins; 0/Proteins; 0/Tumor Suppressor Proteins; 0/mechanistic target of rapamycin complex 1; 4JG2LF96VF/tuberous sclerosis complex 2 protein; EC Serine-Threonine Kinases; EC Ligases

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

Previous Document:  Retrobiosynthetic approach delineates the biosynthetic pathway and the structure of the acyl chain o...
Next Document:  S-glutathionylation of the Na,K-ATPase catalytic ? subunit is a determinant of the enzyme redox sens...