GSK3  is a negative regulator of the transcriptional coactivator MAML1

Abstract

Glycogen synthase kinase 3β (GSK3β) is involved in several cellular signaling systems through regulation of the activity of diverse transcription factors such as Notch, p53 and β-catenin. Mastermind-like 1 (MAML1) was originally identified as a Notch coactivator, but has also been reported to function as a transcriptional coregulator of p53, β-catenin and MEF2C. In this report, we show that active GSK3β directly interacts with the MAML1 N-terminus and decreases MAML1 transcriptional activity, suggesting that GSK3β might target a coactivator in its regulation of gene expression. We have previously shown that MAML1 increases global acetylation of histones, and here we show that the GSK3 inhibitor SB41, further enhances MAML1-dependent histone acetylation in cells. Finally, MAML1 translocates GSK3β to nuclear bodies; this function requires full-length MAML1 protein.

Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

“…We found that EC-educated MniPSC-MPP downregulated targets of the Wnt/β-catenin pathway relative to EC-naive MniPSC-MPP, which is not surprising given that ECs express Wnt pathway inhibitors DKK1 (47), DKK3 (15), IGFPB2 (48), and IGFBP3 (49). Wnt signaling has been shown to regulate the Notch pathway in normal (50)(51)(52) and malignant hematopoiesis (53,54). The intersection between Wnt and Notch signaling and modulation of their equilibrium in the context of a vascular setting may reveal the precise balance required for endothelial to hematopoietic transition and definitive HSC emergence.…”

Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

“…Saint Just Ribeiro et al (2009) found that activated GSK-3b could interact with the Maml1 N-terminus to decrease its transcriptional activity. Espinosa et al (2003) found that lithium upregulated the Hes1 mRNA in NIH-3T3 and HEK-293T cells.…”

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

“…GSK3β was demonstrated to phosphorylate and negatively regulate Notch2 195 and the Notch co-activator MAML1. 196 Conversely, GSK3β has been shown to phosphorylate and positively regulate Notch1 in different models. 197 These observations imply that pharmacological inhibition of Wnt or PI3K–AKT has the potential to also modulate Notch and HH, resulting in desirable or undesirable effects.…”