Changes
/* GSK-3 Inhibition */
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.
* Wnt signaling inhibits GSK3 activityExposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a consequenceresult, beta-catenin would no longer be phosphorylated is dephosphorylated and accumulate escapes the ubiqduitylation-dependent destruction machinery. * Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to form nuclear complexes the nucleus, where it can associate with the TCF/LEF factorsLEFs and become a transcriptional transactivator.
'''[[More details on GSK-3]]'''
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive.
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.
'''Conclusion'''
== Conclusions ==
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