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/* Conclusions */
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== GSK-3 Inhibition==
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified.
* 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 activity. As a consequence, beta-catenin would no longer be phosphorylated and accumulate to form nuclear complexes with TCF/LEF factors.
'''Key points'''
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation.
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway.
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved.
* Thus our goal is to stop the phosphorylation of the serine and threonine residue.
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP.
[[image:GSK3_phosphorylation|300 px|thumb|Phosphorylation mechanism]]
* The common phosphorylation procedure through ATP to ADP conversion we can’t stop.
* Thus we have to target on the Oxygen atom I the Phosphorous group, marked in the red circles in the figure above. As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation
== Conclusions ==
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