GSK3 as a Sensor Determining Cell Fate in the Brain

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.

Interaction of PDK1 with Phosphoinositides Is Essential for Neuronal Differentiation but Dispensable for Neuronal Survival

“…We show that the reduced levels of PKB activation are sufficient to support the phosphorylation and inhibition of some cellular targets promoting apoptosis, such as the FOXO1 transcription factor (48) or the GSK3 kinase (49). In contrast, the reduced levels of PKB activation achieved in PDK1 K465E/K465E neurons are rate limiting for PRAS40 and TSC2 phosphorylation.…”

Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

“…Indeed, the MAPK/ERK pathway is one of the best-studied pathways, which links to very fundamental cell processes, i.e., cell growth, differentiation, migration, and apoptosis [58][59][60][61]. Similarly, GSK3β functions in several cell events via self-phosphorylation, and in the brain, it works as a sensor to determine cell fate [62]. The activation of the MAPK pathway by different stimuli may lead to GSK3β inhibition [58,59,63].…”

Regulation of Cell Fate in the Brain by GSK3

“…This involves dynamic reorganization of microtubules by a variety of microtubule-binding proteins. Several of these are directly phosphorylated and regulated by GSK3, including Tau, CRMP2, MAP1B, MAP2C, CLASP2, pVHL and APC (for reviews, see [145,146]). Phosphorylation of many of these substrates by GSK3 reduces their ability to bind microtubules, thus making them less stable.…”