scholarly journals GSK3 as a Regulator of Cytoskeleton Architecture: Consequences for Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2092
Author(s):  
Daria Hajka ◽  
Bartosz Budziak ◽  
Łukasz Pietras ◽  
Przemysław Duda ◽  
James A. McCubrey ◽  
...  
Keyword(s):  
Growth And Development ◽  
Glycogen Synthase ◽  
Vital Role ◽  
Cell Polarization ◽  
Glycogen Synthase Kinase 3 ◽  
Directional Migration ◽  
Cellular Physiology ◽  
A Cell ◽  
Health And Disease ◽  
Migration Of Cells

Glycogen synthase kinase 3 (GSK3) was initially isolated as a critical protein in energy metabolism. However, subsequent studies indicate that GSK-3 is a multi-tasking kinase that links numerous signaling pathways in a cell and plays a vital role in the regulation of many aspects of cellular physiology. As a regulator of actin and tubulin cytoskeleton, GSK3 influences processes of cell polarization, interaction with the extracellular matrix, and directional migration of cells and their organelles during the growth and development of an animal organism. In this review, the roles of GSK3–cytoskeleton interactions in brain development and pathology, migration of healthy and cancer cells, and in cellular trafficking of mitochondria will be discussed.

scholarly journals Daydreamer, a Ras effector and GSK-3 substrate, is important for directional sensing and cell motility

2013 ◽  
Vol 24 (2) ◽  
pp. 100-114 ◽  
Author(s):  
Verena Kölsch ◽  
Zhouxin Shen ◽  
Susan Lee ◽  
Katarzyna Plak ◽  
Pouya Lotfi ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Leading Edge ◽  
Adaptor Proteins ◽  
Cell Polarization ◽  
Glycogen Synthase Kinase 3 ◽  
Dynamic Regulation ◽  
Multiple Substrates ◽  
Directional Movement ◽  
Phosphoinositide 3 Kinase ◽  
Kinetics Of

How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA− cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA− cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA− cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.

scholarly journals The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

2015 ◽  
Vol 43 (4) ◽  
pp. 687-689 ◽  
Author(s):  
Maria A. O’Connell ◽  
John D. Hayes
Keyword(s):  
Small Molecules ◽  
Glycogen Synthase ◽  
Antioxidant Response ◽  
Research Area ◽  
Glycogen Synthase Kinase 3 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Ubiquitin Protein Ligase ◽  
Health And Disease ◽  
Transcription Factor Nuclear Factor

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3)−β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.

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