Abstract
Glycogen synthase kinase-3 (GSK-3) unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular basis of these disorders. GSK-3 is ubiquitously expressed and, unusually, constitutively active in resting, unstimulated cells. In mammals, GSK-3α and β are each expressed widely at both the RNA and protein levels although some tissues show preferential levels of some of the two proteins. Neither gene appears to be acutely regulated at the transcriptional level, whereas the proteins are controlled posttranslationally, largely through protein-protein interactions or by posttranslational regulation. Control of GSK-3 activity thus occurs by complex mechanisms that are each dependent upon specific signalling pathways. Furthermore, GSK-3 appears to be a cellular nexus, integrating several signalling systems, including several second messengers and a wide selection of cellular stimulants. This paper will focus on the different ways to control GSK-3 activity (phosphorylation, protein complex formation, truncation, subcellular localization, etc.), the main signalling pathways involved in its control, and its pathological deregulation.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a CMGC serine/ threonine protein kinase initially described as one of the kinases that phosphorylates and inhibits glycogen synthase [1]
GSK-3 has been highly conserved during evolution, and homolog genes have been identified in virtually every eukaryotic genome investigated, including species, such as Dictyostelium discoideum, Xenopus laevis, or Drosophila melanogaster [14,15,16]
This ability of GSK-3β to bind two different proteins with high specificity via the same binding site is mediated by the conformational plasticity of the 285–299 loop, while some residues in this versatile binding site are involved in interactions with both axin and FRAT; others are involved uniquely with one or the other [26]
Summary
Glycogen synthase kinase-3 (GSK-3) is a CMGC serine/ threonine protein kinase initially described as one of the kinases that phosphorylates and inhibits glycogen synthase [1]. It is widely accepted though that GSK-3 plays an important role in various essential physiological processes, such as development, cell cycle, or apoptosis [2]. GSK-3 dysfunction has been associated with brain pathological conditions, such as Alzheimer’s disease (AD) [11, 12] or prion neurotoxicity [13]. The deep knowledge of the role of both GSK-3 isoforms in brain metabolism will allow us to understand their contribution to neurodegenerative processes. GSK-3 unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular bases of these disorders. GSK-3 appears to be a cellular nexus, integrating several signalling systems, including numerous second messengers and a wide selection of cellular stimulants
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
