The beta catenin TCF complex is an important

The beta-catenin/TCF complex is an important target in the Wnt/beta-catenin pathway. This complex has proven challenging to target. However, natural inhibitors of this complex have been identified. One group of inhibitors is called the inhibitors of Wnt response (IWR-1/2). IWR-1/2 targets Axin and stabilizes it [488], [499]. XAV939 is another inhibitor that also targets and stabilizes Axin [489]. These inhibitors, IWR-1/2 and XAV939, act by suppressing the enzyme tankyrase that results in beta-catenin degradation. Tankyrase is a poly-ADP ribosylase and normally poly-ADP ribosylates Axin1/2 that results in its turnover. Axin becomes stabilized when tankyrase is inhibited. This results in the destabilization of beta-catenin and inhibition of Wnt signaling. Axin is poly-ADP ribosylated that is recognized by the ring finger protein 146 (RNF146). This results in the ubiquitination and subsequent degradation of Axin. CK1 also exerts effects on the stability of beta-catenin. CK1 activators, such as the FDA-approved drug Pyrvinium, will also modulate the stability of beta-catenin [491]. The enzyme Porc (short for porcupine) is a transmembrane O-acyltransferase in the endoplasmic reticulum. Porc is essential for Wnt palmitoylation and maturation [500], [501]. Lipid-free Wnts are not secreted. Suppression of Porc activity with the IWP2 phosphocreatine inhibited Wnt palmitoylation which also suppressed Wnt/beta-catenin signaling, and Wnt-C59 is a Wnt/Porc inhibitor which modifies Wnt activity. Wnt-C59 was determined to suppress the growth and stemness properties of nasopharyngeal (SUNE1 and HNE1) carcinoma cell lines [502].
Summary The roles of GSK-3 in biological processes have evolved significantly since it was first identified as an enzyme that phosphorylated and inactivated GS, a key metabolic enzyme. GSK-3 is clearly a key moon-lighting enzyme that has critical roles in many biological processes and diseases. As expected, GSK-3 was shown to be important in metabolic diseases such as diabetes and cardiovascular diseases. GSK-3 was demonstrated to be the target of lithium that is a key remedy in various neurological disorders. GSK-3 was identified as playing key roles in Wnt/beta-catenin signaling which is frequently aberrantly regulated in CRC due to mutations in the pathway at APC genes as well as mutations at the sites of phosphorylation of beta-catenin by GSK-3 and CK-1. GSK-3 is regulated by many kinases, including: Akt, PKA, Src, ERK, p38MAPK, Src, Fyn, PYK2 and others. In addition, GSK-3 activity is regulated by phosphatases such as PP1 and PP2A. Thus there are many biochemical mechanisms to regulate GSK-3 activity. Due to the high frequency of mutations of PIK3CA (PI3Kalpha) and PTEN in human cancers, as well as aberrant expression of upstream growth factor receptors, Akt is frequently activated in human cancer that can result in abnormal Akt activity that in turn will normally extinguish GSK-3 activity. These effects on GSK-3 activity can influence the activity of other pathways such as: Wnt/beta-catenin, Hh and Notch. Moreover, GSK-3 can also serve to prevent Akt activation by phosphorylation of Rictor which results its inability to catalyze the “second” phosphorylation event involved in Akt activation. Thus, there are complicated regulatory loops between Akt-GSK-3-Rictor-Akt that serves to control this critical cascade important in cellular growth and malignant transformation. So we can begin to see how mutations in pathways associated with cellular proliferation can have effects on EMT and developmental pathways. Some of the normal activities of these pathways are “normally coordinated or fine-tuned” by GSK-3. However, in cancer these activities normally controlled by GSK-3 may disappear and have deleterious consequences.
Conflicts of interest
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Acknowledgments JAM, SLA, KL and TF were supported in part by East Carolina University Grant #111104. AMM was supported in part by grants from: MIUR FIRB 2011 (RBAP11ZJFA_001).