Glycogen Synthase Kinase-3 and TBI Figure 1. TBI alters the regulation of GSK-3. A) Schematic diagram showing the GSK-3 cascade. In the absence of Wnt signaling, GSK-3 complexes with APC, Axin, and casein kinase 1a (CK1a) and phosphorylates ß-Catenin (ß-cat) leading to its ubiquitination (Ub) and degradation. B) Upon Wnt binding to the Frizzled-LRP6 receptors, GSK-3 is translocated to the membrane via binding of Disheveled (Dsh) where it can phosphorylate LRP6, and allow for ß-Catenin accumulation and gene expression (via interaction with LEF/TCF transcription factors). C) Growth factor binding can result in Akt-mediated phosphorylation and inactivation of GSK-3. Rats (n = 5/time point) were subjected to TBI and hippocampi removed at various time points for western blot analysis. Representative images of western blots for D) phospho- and total LRP6, F) phospho- and total GSK-3ß, and H) phospho- and total ß-Catenin are shown. E) Summary data shows that TBI causes a transient increase in the phosphorylation of LRP6 on Ser1490. G) The phosphorylation of GSK-3ß on Ser9 is increased in a delayed manner, at a time point consistent with its phosphorylation by Akt. I) ß-Catenin phosphorylation was decreased at time points consistent with GSK-3 translocation to LRP6, but not as a result of GSK-3 phosphorylation. No change in ß-Catenin accumulation was observed. Data are presented as the mean 6 SEM. *, P,0.05 by one-way ANOVA compared to sham animals. doi:10.1371/journal.pone.0024648.g001 PLoS ONE | www.plosone.org 3 September 2011 | Volume 6 | Issue 9 | e24648