Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 ± 27 nM), in an ATP-competitive manner (K i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 μM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3β protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by β-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.Supported by grants from the Comunidad de Madrid, the Fundacion “La Caixa,” the Lilly Foundation, the Spanish Comision Interministerial de Ciencia y Tecnologia, and an institutional grant from the Fundacion Ramon Areces.Peer reviewe

Postmodern management? From facts to fiction in theory and practice

Postmodernism has recently cropped up as a new buzz word in the organization and management sciences, and the purpose of this article is to critically examine its potential value in the discourse of organizations and management. The article starts with a discussion of the concept of postmodernism, showing that it is used; as an indicator of the present epoch (the postmodern age or condition), as a way of capturing a contemporary movement in the arts and literature (an "ism"), and finally as a particular mode of discourse. With the help of some of the basic postmodern assumptions and concepts, the article then proceeds to a review of contemporary Swedish organization and management theory and praxis. The review shows that the present situation can be characterized by the deconstruction of organization structures, the rejection of grand strategies, an emphasis on expressivism and the importance of coding. In the last section of the article the usefulness of the postmodern perspective for managerial purposes is discussed. It is also claimed that parallel with this deconstruction of organization structures and positive norms, it is possible to discern the reconstruction of social and cultural values developed in an open discourse and resulting in collective reason -- and morals.Postmodernism deconstruction expressivism codification credibility corporate surfaces