GSK-3-mediated regulation of cellular functions and signaling pathways

Abstract

Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine kinase that has emerged as a central regulator of diverse cellular signaling networks and physiological processes. Originally recognized for its role in glycogen metabolism, GSK-3 is now known to participate in the regulation of gene expression, metabolism, proliferation, differentiation, development, apoptosis, cellular adhesion, migration, and neuronal function. Its activity is controlled through multiple regulatory mechanisms, including inhibitory phosphorylation and modulation of protein complexes, enabling GSK-3 to respond dynamically to extracellular and intracellular signals. The two paralogues, GSK-3α and GSK-3β, share considerable structural similarity but may exhibit distinct and sometimes overlapping biological functions. Dysregulated GSK-3 signaling has been associated with neurological and neurodegenerative disorders, metabolic and inflammatory diseases, and cancer. Although pharmacological inhibition of GSK-3 has therefore attracted considerable therapeutic interest, clinical translation remains challenging because of limited isoform selectivity, context-dependent biological effects, and the complex physiological functions of this kinase. Recent findings further demonstrate that GSK-3 can regulate central cellular processes through distinct isoform-dependent mechanisms, emphasizing the importance of understanding its spatial, temporal, and substrate-specific regulation. A comprehensive characterization of GSK-3α and GSK-3β may consequently facilitate the development of more selective and clinically effective therapeutic strategies.