scholarly journals Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1110 ◽  
Author(s):  
Przemysław Duda ◽  
Shaw M. Akula ◽  
Stephen L. Abrams ◽  
Linda S. Steelman ◽  
Alberto M. Martelli ◽  
...  
Keyword(s):  
Natural Products ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glycogen Synthase ◽  
Human Cancer ◽  
Glycogen Synthase Kinase 3 ◽  
Pharmaceutical Companies ◽  
Biochemical Processes ◽  
Multiple Substrates ◽  
Mtorc1 Pathway

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

2001 ◽  
Vol 77 (1) ◽  
pp. 94-102 ◽  
Author(s):  
Darren A. E. Cross ◽  
Ainsley A. Culbert ◽  
Katy A. Chalmers ◽  
Laura Facci ◽  
Stephen D. Skaper ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

2008 ◽  
Vol 77 (1) ◽  
pp. 94-102 ◽  
Author(s):  
Darren A. E. Cross ◽  
Ainsley A. Culbert ◽  
Katy A. Chalmers ◽  
Laura Facci ◽  
Stephen D. Skaper ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

2000 ◽  
Vol 7 (10) ◽  
pp. 793-803 ◽  
Author(s):  
Matthew P Coghlan ◽  
Ainsley A Culbert ◽  
Darren AE Cross ◽  
Stacey L Corcoran ◽  
John W Yates ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals PAIN-less identification and evaluation of small molecule inhibitors against protein tyrosine phosphatase 1B

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1220-1224 ◽  
Author(s):  
Hamid R. Nasiri ◽  
Philipp Mracek ◽  
Steffen K. Grimm ◽  
Janine Gastaldello ◽  
Adrian Kolodzik ◽  
...  
Keyword(s):  
Natural Products ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Set Up ◽  
Assay Interference

A miniaturized assay was set up to test a set of natural products against protein tyrosine phosphatase 1B (PTP1B). By using several read-out and counter assays, berberine and palmatine were identified as PAINS (pan-assay interference compounds) and α-TOS as a novel inhibitor of PTP1B.

Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3

2013 ◽  
Vol 85 (7) ◽  
pp. 965-976 ◽  
Author(s):  
Sooho Lee ◽  
Woo Kyeom Yang ◽  
Ji Ho Song ◽  
Young Min Ra ◽  
Jin-Hyun Jeong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Glycogen Synthase ◽  
Small Molecule Inhibitor ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Molecule Inhibitor

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 Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3

2006 ◽  
Vol 26 (15) ◽  
pp. 5784-5796 ◽  
Author(s):  
Alexander Hergovich ◽  
Joanna Lisztwan ◽  
Claudio R. Thoma ◽  
Christiane Wirbelauer ◽  
Robert E. Barry ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Glycogen Synthase ◽  
Human Cancer ◽  
Suppressor Gene ◽  
Binding Activity ◽  
Glycogen Synthase Kinase ◽  
Normal Operation ◽  
Glycogen Synthase Kinase 3

ABSTRACT Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is linked to the development of tumors of the eyes, kidneys, and central nervous system. VHL encodes two gene products, pVHL30 and pVHL19, of which one, pVHL30, associates functionally with microtubules (MTs) to regulate their stability. Here we report that pVHL30 is a novel substrate of glycogen synthase kinase 3 (GSK3) in vitro and in vivo. Phosphorylation of pVHL on serine 68 (S68) by GSK3 requires a priming phosphorylation event at serine 72 (S72) mediated in vitro by casein kinase I. Functional analysis of pVHL species carrying nonphosphorylatable or phosphomimicking mutations at S68 and/or S72 reveals a central role for these phosphorylation events in the regulation of pVHL's MT stabilization (but not binding) activity. Taken together, our results identify pVHL as a novel priming-dependent substrate of GSK3 and suggest a dual-kinase mechanism in the control of pVHL's MT stabilization function. Since GSK3 is a component of multiple signaling pathways that are altered in human cancer, our results further imply that normal operation of the GSK3-pVHL axis may be a critical aspect of pVHL's tumor suppressor mechanism through the regulation of MT dynamics.

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