The role of glycogen synthase kinase-3β in normal haematopoiesis, angiogenesis and leukaemia

Glycogen synthase kinase 3 beta (GSK-3 beta) was one of the first kinases identified and studied, initially for its role in the regulation of glycogen synthesis. Over the past decade, interest in GSK-3 beta has grown far beyond glycogen metabolism, and this is due in large measure to the critical role that GSK-3 beta plays in the regulation of many other cellular processes, particularly cell proliferation and apoptosis. GSK-3 beta has been shown to regulate the proteolysis and sub-cellular compartmentalization of a number of proteins directly involved in the regulation of cell cycling, proliferation, differentiation and apoptosis. GSK-3 beta also regulates the degradation of proteins that regulate gene expression and thus affects a variety of important cell functions. Specifically, GSK-3 beta controls the degradation of beta-catenin, the main effector of Wnt that regulates haematopoiesis and stem cell function. In this case GSK-3 beta is a negative regulator of Wnt. In contrast, GSK-3 beta positively regulates NF-kappa B, another important biochemical pathway also involved in the regulation of multiple aspects of normal and aberrant haematopoiesis. GSK-3 beta regulates degradation of I kappa B, a central inhibitor of NF-kappa B. In this way, GSK-3 beta acts to control the resistance of leukaemic cells to chemotherapy through the modulation of NF-kappa B, a critical factor in maintaining leukaemic cell growth. In addition, GSK-3 beta regulates the pro-inflammatory activity of NF-kappa B. As GSK-3 beta is a pleiotropic regulator, inhibitors may increase the range of novel anti-leukaemic and anti-inflammatory drugs that control immune response.