GSK3 as a Regulator of Cytoskeleton Architecture: Consequences for Health and Disease

Abstract

Glycogen synthase kinase 3 (GSK3) was initially isolated as a critical protein in energy metabolism. However, subsequent studies indicate that GSK-3 is a multi-tasking kinase that links numerous signaling pathways in a cell and plays a vital role in the regulation of many aspects of cellular physiology. As a regulator of actin and tubulin cytoskeleton, GSK3 influences processes of cell polarization, interaction with the extracellular matrix, and directional migration of cells and their organelles during the growth and development of an animal organism. In this review, the roles of GSK3–cytoskeleton interactions in brain development and pathology, migration of healthy and cancer cells, and in cellular trafficking of mitochondria will be discussed.

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

“…Altogether, this evidence supports a link between GSK3β, Na v channels, and neuronal cytoskeletal components during neuronal morphogenesis, cell morphological reorganization, cell motility, migration, and the transport of cargo (e.g., mitochondria) [181,183,190,191].…”

“…Many MAPs are substrates for GSK3β [174,[176][177][178][179]. Therefore, a link is likely between GSK3β, Na + channels, and cytoskeleton dynamics [26,[180][181][182][183]. Additionally, inhibition of GSK3 prevents accumulation of the actin-related protein 2/3 complex (Arp2/3) in cellular extensions.…”

“…Additionally, inhibition of GSK3 prevents accumulation of the actin-related protein 2/3 complex (Arp2/3) in cellular extensions. Arp2/3 binds to the existing F-actin filament and initiates new filament creation in dendritic spines, which results in spine volume expansion [183][184][185][186].…”

Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model

“…GSK3 signaling is important during neural development. Molecules involved in GSK3 signaling pathways regulate gene expression, protein synthesis, neurogenesis, neuronal migration, cell polarization, dendritic orientation, and structural plasticity of the dendritic spines [ 44 , 79 , 80 , 81 ]. The striatal MSNs in the Het Disc1 mice showed reduced dendritic complexity and spine density, reflecting the consequence of reduced GSK3 levels [ 30 ].…”

Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

“…Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase that plays a role in a diversity of intracellular signaling pathways and biological activities in development and throughout adulthood. Dysregulation of GSK3 is implicated in many major diseases, including cancer, inflammation, diabetes, cardiac hypertrophy and an array of CNS disorders (see reviews by Beurel et al, 2015;Ahmad and Woodgett, 2020;Hajka et al, 2021). In terms of brain disorders, GSK3 has been strongly implicated in, for example, sleep disorder, psychiatric illness, neurodevelopmental disorders including autism, intellectual disability, epilepsy and neurodegenerative disorders, in particular Alzheimer's disease (see reviews by Jaworski et al, 2019;Jaworski, 2020;Silva-García et al, 2020;Rizk et al, 2021;Sayas and Ávila, 2021).…”