ERK/Cdk5 axis regulates diabetes-related PPARγ phosphorylation

 

Insulin resistance, caused by obesity, increases the risk of type 2 diabetes. It has been reported that cyclin-dependent kinase 5 (Cdk5) induced phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at serine 273 is a key stimulator of diabetogenic gene expression. Therefore, PPARγ has become a main target of anti-diabetic drugs. Recently, Banks et al. discovered that ERK/Cdk5 axis is involved in regulation PPARγ activities, and the inhibition of extracellular signal-regulated kinase (ERK) and MAP kinase/ERK kinase (MEK) leads to the improvement of insulin resistance. The letter was published on Nature.

 

Researchers generated adipose tissue-specific Cdk5-deficient mice (Cdk5-KO), which was found had high level of PPARγ phosphorylation at serine 273 and severe insulin resistance, compared with wild-type (WT) mice. Further investigation shows Cdk5 has ability to suppress ERKs, which causes PPARγ S273 phophorylation, by binding to new site of MEK. Then, the efficacy of pharmacologic ERK and MEK inhibitors was tested. Both PD0325901 and Trametinib/GSK1120212 treatments contributed to a improvement in glucose tolerance and a increase insulin-sensitivity. The results indicate that MEK/ERK inhibitors have promising effect to be applied in therapeutic treatment of type 2 diabetes.

 

Reference:
Nature. 2014 Nov 17;10.1038/nature13887

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Cat.No.	Product Name	Information
S1036	Mirdametinib (PD0325901)	Mirdametinib (PD0325901) is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 2.
S2673	Trametinib (GSK1120212)	Trametinib (GSK1120212, JTP-74057) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2. Trametinib activates autophagy and induces apoptosis.

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PPAR MEK ERK CDK