The Role of Glycogen Synthase Kinase-3β in Normal Haematopoiesis, Angiogenesis and Leukaemia

T.      Holmes; T.   A.   O'Brien; R.      Knight; R.      Lindeman; G.      Symonds; A.      Dolnikov

doi:10.2174/092986708784638834

Abstract

Glycogen synthase kinase 3 beta (GSK-3β) 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-3β has grown far beyond glycogen metabolism, and this is due in large measure to the critical role that GSK-3β plays in the regulation of many other cellular processes, particularly cell proliferation and apoptosis. GSK-3β 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-3β also regulates the degradation of proteins that regulate gene expression and thus affects a variety of important cell functions. Specifically, GSK-3β controls the degradation of β- catenin, the main effector of Wnt that regulates haematopoiesis and stem cell function. In this case GSK-3β is a negative regulator of Wnt. In contrast, GSK-3β positively regulates NF-κB, another important biochemical pathway also involved in the regulation of multiple aspects of normal and aberrant haematopoiesis. GSK-3β regulates degradation of IκB, a central inhibitor of NF-κB. In this way, GSK-3β acts to control the resistance of leukaemic cells to chemotherapy through the modulation of NF-κB, a critical factor in maintaining leukaemic cell growth. In addition, GSK-3β regulates the pro-inflammatory activity of NF-κB. As GSK-3β is a pleiotropic regulator, inhibitors may increase the range of novel anti-leukaemic and anti-inflammatory drugs that control immune response.

Keywords: Haematopoiesis, angiogenesis, leukaemogenesis, β-catenin, NF-κB, Wnt, haematopoietic stem cell, GSK-3β inhibition