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Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase. It was initially identified as a regulator (inhibitor) of glycogen synthesis. It has since been recognized as a multifunctional kinase with a variety of roles both in invertebrates and in vertebrate cells.
Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase. It was initially identified as a regulator (inhibitor) of glycogen synthesis . It has since been recognized as a multifunctional kinase with a variety of roles both in invertebrates and in vertebrate cells. In mammals (humans included), there are two closely related isoforms of the kinase: GSK3α and GSK3β . They share ~98% identity in their kinase domains, but they have distinct substrate preferences, and their cellular functions are, at least partially, non-redundant . The β isoform predominates in the majority of cells, and it is also more studied. GSK3 requires phosphorylation on tyrosine 216 (β isoform) or 279 (α isoform) for maximal activity. As a constitutively active kinase, it is oftentimes inhibited in response to upstream signals by phosphorylation of S9 (GSK3β) or S21 (GSK3βα). As a sensor of growth factors (e.g., insulin, transforming growth factor-β, epidermal growth factor, nerve growth factor, and brain-derived neurotropic factor) and other extracellular stimuli GSK3 is a master switch kinase regulating various aspects of cellular function such as growth, repair, mobility, and survival. Therefore, it is not surprising that dysregulation of GSK3 activity is observed in many pathophysiological processes, including the development of cancer, and neurodegenerative and psychiatric disorders (for review see ). This also makes GSK3 an attractive therapeutic target, and intensive efforts have been undertaken to discover clinically relevant selective GSK3 inhibitors . However, the pleiotropic functions of the kinase pose major obstacles in developing effective treatments without adverse effects.
In the still-increasing list of GSK3 substrates, there are, among others, proteins engaged in the regulation of actin cytoskeleton dynamics (e.g., Rho family members and related GTPases), microtubule-associated proteins (MAPs, e.g., Tau and collapsin response mediator protein 2 (CRMP 2)) and adhesion of cells to extracellular matrix (e.g., focal adhesion kinase, FAK) . Acting through these substrates, GSK3 can influence cell polarization and directional migration, as well as intracellular trafficking of mitochondria and vesicular structures. The migration of cells is a fundamental process, especially important in the development of an organism. Although not all differentiated adult cell types migrate in vivo, almost all of them exhibit some form of spatial segregation of structures and functions and require some form of organelles’ trafficking. This, in turn, requires the orchestration of activities of several signaling pathways. Since GSK3 lies at the crossroads of these pathways, it can be viewed as one of the coordinators/integrators of complex processes of cellular dynamics.
2. GSK3–Cytoskeleton Interplay in Brain Development and Pathology
3. GSK3–Cytoskeleton Interplay in Cell Motility and Migration of Cancer Cells
For many years, scientists and clinicians have focused their attention on the biochemical mechanisms of GSK3 and its involvement in various diseases. Additionally, for many years, this kinase has been indicated as a potential target of various therapies, and thus, efforts have been concentrated on exploring the possibility of using GSK3 inhibitors as potential drugs. Unfortunately, stunning success has not been frequently observed. In the way of achieving success stands probably the very reason why GSK3 is such an interesting object of research: multifunctionality of the kinase and complexity of functional cross-talks between GSK3 and its up- and downstream effectors. Global inhibition or overexpression of GSK3 in the cell rarely produces the desired results, often leading instead to serious side effects. Thus, although numerous GSK3 inhibitors have been evaluated, they relatively rarely reach Phase-2 clinical trials. The conclusions drawn in the experimental papers reviewed in our paper suggest that also in the case of the cytoskeleton-related cellular roles of GSK3, e.g., regulation of division, migratory potential, and the polarity of the cell, and maintaining transport of cargo along the cytoskeleton, a precise balance between activation and inhibition of the kinase and its proper spatiotemporal distribution is required. Thus, focusing on finding methods that enable only local alteration of activity/concentration of this protein, or targeting a specific downstream target or an upstream regulator of GSK3 might be a more promising approach than changing the total cellular activity/concentration of the kinase. Therefore, a comprehensive description of the cellular interaction networks of GSK3 might be crucial to identify novel protein targets with the highest therapeutic potential for the treatment of GSK3-related diseases.
The entry is from 10.3390/cells10082092
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