Protein levels of β-catenin and activation state of glycogen synthase kinase-3β in major depression. A study with postmortem prefrontal cortex

2012 ◽  
Vol 136 (1-2) ◽  
pp. 185-188 ◽  
Author(s):  
Félicien Karege ◽  
Nader Perroud ◽  
Sandra Burkhardt ◽  
Rafael Fernandez ◽  
Eladia Ballmann ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Major Depression ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Levels

scholarly journals Glycogen synthase kinase 3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1

2010 ◽  
Vol 206 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Sanhua Leng ◽  
Wenshuo Zhang ◽  
Yanbin Zheng ◽  
Ziva Liberman ◽  
Christopher J Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Insulin Receptor Substrate ◽  
Glycogen Synthase Kinase 3Β ◽  
Proteasome Degradation ◽  
Protein Levels

High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3β (GSK3β or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine332 phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine332 to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3β was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3β contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.

scholarly journals SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia

2017 ◽  
Vol 292 (18) ◽  
pp. 7452-7461 ◽  
Author(s):  
Tomeka Suber ◽  
Jianxin Wei ◽  
Anastasia M. Jacko ◽  
Ina Nikolli ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Proteasomal Degradation ◽  
Lung Epithelial Cells ◽  
Glycogen Synthase Kinase ◽  
Acceptor Site ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Subunit ◽  
Protein Levels ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein

Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skp1/Cullin-1/F-box (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial cells through lysine 183 as an acceptor site for K48 polyubiquitination. We have identified FBXO17 as an F-box protein subunit that recognizes and mediates GSK3β polyubiquitination. Both endogenous and ectopically expressed FBXO17 associate with GSK3β, and its overexpression leads to decreased protein levels of GSK3β. Silencing FBXO17 gene expression increased the half-life of GSK3β in cells. Furthermore, overexpression of FBXO17 inhibits agonist-induced release of keratinocyte-derived cytokine (KC) and interleukin-6 (IL-6) production by cells. Thus, the SCFFBXO17 E3 ubiquitin ligase complex negatively regulates inflammation by targeting GSK3β in lung epithelia.

Sign in / Sign up

Export Citation Format

Share Document