PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes

2014 ◽  
Vol 464 (1) ◽  
pp. 145-156 ◽  
Author(s):  
James W. Robinson ◽  
Iryna Leshchyns’ka ◽  
Hovik Farghaian ◽  
William E. Hughes ◽  
Vladimir Sytnyk ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Vesicular Trafficking ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Lipid Kinase ◽  
Phosphatidylinositol 4 ◽  
The Brain

Glycogen synthase kinase 3 (GSK3) regulates neurotransmission in the brain, but the substrates mediating this are unclear. In the present paper, we report the lipid kinase phosphatidylinositol 4-kinase II α (PI4KIIα) is a novel substrate of GSK3 that switches vesicular trafficking from secretory/recycling pathways to the lysosome in neurons.

scholarly journals Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain

2010 ◽  
Vol 115 (4) ◽  
pp. 974-983 ◽  
Author(s):  
Marc P. M. Soutar ◽  
Woo-Yang Kim ◽  
Ritchie Williamson ◽  
Mark Peggie ◽  
Charles James Hastie ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Substrate Preference ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
The Brain

scholarly journals Glycogen Synthase Kinase-3β: A Mediator of Inflammation in Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jari Koistinaho ◽  
Tarja Malm ◽  
Gundars Goldsteins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Immune Defense ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Normal Brain ◽  
Brain Functions ◽  
The Brain

Proliferation and activation of microglial cells is a neuropathological characteristic of brain injury and neurodegeneration, including Alzheimer's disease. Microglia act as the first and main form of immune defense in the nervous system. While the primary function of microglia is to survey and maintain the cellular environment optimal for neurons in the brain parenchyma by actively scavenging the brain for damaged brain cells and foreign proteins or particles, sustained activation of microglia may result in high production of proinflammatory mediators that disturb normal brain functions and even cause neuronal injury. Glycogen synthase kinase-3βhas been recently identified as a major regulator of immune system and mediates inflammatory responses in microglia. Glycogen synthase kinase-3βhas been extensively investigated in connection to tau and amyloidβtoxicity, whereas reports on the role of this enzyme in neuroinflammation in Alzheimer's disease are negligible. Here we review and discuss the role of glycogen synthase-3βin immune cells in the context of Alzheimer's disease pathology.

scholarly journals Functional Implications of Glycogen Synthase Kinase-3-Mediated Tau Phosphorylation

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Diane P. Hanger ◽  
Wendy Noble
Keyword(s):  
Glycogen Synthase ◽  
Regulatory Element ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphorylation Sites ◽  
Pick Bodies ◽  
Functional Implications ◽  
The Brain

Tau is primarily a neuronal microtubule-associated protein that has functions related to the stabilisation of microtubules. Phosphorylation of tau is an important dynamic and regulatory element involved in the binding of tau to tubulin. Thus, highly phosphorylated tau is more likely to be present in the cytosolic compartment of neurons, whereas reduced phosphate burden allows tau to bind to and stabilise the microtubule cytoskeleton. Highly phosphorylated forms of tau are deposited in the brain in a range of neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal lobar degeneration associated with Pick bodies. A key candidate kinase for both physiological and pathological tau phosphorylation is glycogen synthase kinase-3 (GSK-3). Multiple phosphorylation sites have been identified on tau exposed to GSK-3in vitroand in cells. In this review, we highlight recent data suggesting a role for GSK-3 activity on physiological tau function and on tau dysfunction in neurodegenerative disease.

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors

2020 ◽  
Vol 20 (17) ◽  
pp. 1522-1534 ◽  
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
High Specificity ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Important Target ◽  
The Brain

: Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer’s disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer’s disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer’s disease.

scholarly journals Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

2016 ◽  
Vol 128 (33) ◽  
pp. 9753-9757 ◽  
Author(s):  
Steven H. Liang ◽  
Jinshan Michael Chen ◽  
Marc D. Normandin ◽  
Jeanne S. Chang ◽  
George C. Chang ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
The Brain
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