The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ
Open accessAbstract
Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
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Cited by
FDA-approved small-molecule kinase inhibitors
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The macrophage switch in obesity development
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Metadata
- Authors
- Banks, A. S., McAllister, F. E., Camporez, J. P. G., Zushin, P.-J. H., Jurczak, M. J., Laznik-Bogoslavski, D., Shulman, G. I., Gygi, S. P., & Spiegelman, B. M.
- Venue
- Nature
- Published
- 2014-11-17
- Volume
- 517
- Issue
- 7534
- Pages
- 391-395
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2055494790
- Cited by
- 297
- References
- 8
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
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- Banks, A. S., McAllister, F. E., Camporez, J. P. G., Zushin, P.-J. H., Jurczak, M. J., Laznik-Bogoslavski, D., Shulman, G. I., Gygi, S. P., & Spiegelman, B. M. (2015). An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature. https://doi.org/10.1038/nature13887
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