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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.
Pubmed: (View Article at PubMed) PMID:21489990
DOI: Full-text: DOI:10.1074/jbc.M111.220962

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.


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CRRD Object Information
CRRD ID: 5131647
Created: 2011-05-09
Species: All species
Last Modified: 2011-05-09
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.