Abstract
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. It mediates these functions by phosphorylating a wide range of substrates involved in gene transcription, metabolism, apoptosis, cytoskeletal dynamics, signal transduction, lipid membrane dynamics, and trafficking, amongst others. This complicated list of diverse substrates generally follow a more simple pattern: substrates negatively regulated by GSK3-mediated phosphorylation favor a proliferative/survival state, while substrates positively regulated by GSK3 favor a more differentiated/functional state. Accordingly, GSK3 activity is higher in differentiated cells than undifferentiated cells and physiological (Wnt, growth factors) and pharmacological inhibitors of GSK3 promote the proliferative capacity of embryonic stem cells. In the brain, the level of GSK3 activity influences neural progenitor cell proliferation/differentiation in neuroplasticity and repair, as well as efficient neurotransmission in differentiated adult neurons. While defects in GSK3 activity are unlikely to be the primary cause of neurodegenerative diseases, therapeutic regulation of its activity to promote a proliferative/survival versus differentiated/mature functional environment in the brain could be a powerful strategy for treatment of neurodegenerative and other mental disorders.
Highlights
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis
When analyzing the substrates of GSK3, a pattern emerges whereby those that are negatively regulated by GSK3 are commonly involved in promoting proliferation and/or survival, while substrates that are positively regulated by phosphorylation are predominantly expressed in differentiated post-mitotic neurons and are required for efficient function of mature neurons
The former substrates include pro-proliferation transcription factors or pro-survival proteins targeted for ubiquitin-mediated degradation by GSK3, while the latter are often cytoskeleton-associated proteins
Summary
Glycogen synthase kinase 3 (GSK3) is an unusual serine/threonine kinase that controls many neuronal functions, including neurite outgrowth, synapse formation, neurotransmission, and neurogenesis It mediates these functions by phosphorylating a wide range of substrates involved in gene transcription, metabolism, apoptosis, cytoskeletal dynamics, signal transduction, lipid membrane dynamics, and trafficking, amongst others. Following priming by another kinase (often a Cdk or MAPK), phosphorylation by GSK3 creates a binding site for E3 ubiquitin ligases that ubiquitinate the protein and target it for proteasome-mediated degradation Many of these transcription factors have short halflives, largely due to the actions of GSK3, which is highly active under basal conditions in differentiated cells, including postmitotic neurons. Adaptor protein that mediates signaling downstream of insulin and growth factor receptors
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