RGD Reference Report - Early Growth Response 1 (Egr-1) regulates phosphorylation of microtubule-associated protein tau in mammalian brain. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

Early Growth Response 1 (Egr-1) regulates phosphorylation of microtubule-associated protein tau in mammalian brain.

Authors: Lu, Y  Li, T  Qureshi, HY  Han, D  Paudel, HK 
Citation: Lu Y, etal., J Biol Chem. 2011 Apr 13.
RGD ID: 5131647
Pubmed: PMID:21489990   (View Abstract at PubMed)
PMCID: PMC3121503   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.220962   (Journal Full-text)

In the normal brain, tau protein is phosphorylated at a number of proline- and non-proline directed sites, which reduce tau microtubule binding and thus regulate microtubule dynamics. In Alzheimer disease (AD), tau is abnormally hyperphosphorylated leading to neurofibrillary tangle formation and microtubule disruption, suggesting a loss of regulatory mechanisms controlling tau phosphorylation. Early growth response 1 (Egr-1) is a transcription factor that is significantly upregulated in AD brain. The pathological significance of this upregulation is not known. In this study, we show that lentivirus-mediated overexpression of Egr-1 in rat brain hippocampus and primary neurons in culture activates proline-directed kinase Cdk5, inactivates PP1, promotes tau phosphorylation at both proline-directed S396/404 and non-proline-directed S262 sites, and destabilizes microtubules. Furthermore, in Egr-1-/- mouse brain, Cdk5 activity is decreased, PP1 activity is increased and tau phosphorylation is reduced at both proline-directed and non-proline-directed sites. By using NGF-exposed PC12 cells, we determined that Egr-1 activates Cdk5 to promote phosphorylation of tau and inactivates PP1 via phosphorylation. When Cdk5 is inhibited, tau phosphorylation at both proline- and non-proline directed sites as well as PP1 phosphorylation are blocked, indicating that Egr-1 acts through Cdk5. By using an in vitro kinase assay and HEK-293 cells transfected with tau, PP1, and Cdk5, we show that Cdk5 phosphorylates S396/404 directly. In addition, by phosphorylating and inactivating PP1, Cdk5 promotes tau phosphorylation at S262 indirectly. Our results indicate that Egr-1 is an in vivo regulator of tau phosphorylation and suggest that in AD brain, increased levels of Egr-1 aberrantly activates an Egr-1/Cdk5/PP1 pathway leading to accumulation of hyperphosphorylated tau, thus destabilizing the microtubule cytoskeleton.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  IEP 5131647protein:increased expression:temporal cortex and hippocampus (human)RGD 
Alzheimer's disease  ISOEGR1 (Homo sapiens)5131647; 5131647protein:increased expression:temporal cortex and hippocampus (human)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to growth factor stimulus  IEP 5131647nerve growth factorRGD 

Objects Annotated

Genes (Rattus norvegicus)
Egr1  (early growth response 1)

Genes (Mus musculus)
Egr1  (early growth response 1)

Genes (Homo sapiens)
EGR1  (early growth response 1)


Additional Information