Mitogen-activated Protein Kinase Kinase Inhibition Does Not Block the Stimulation of Glucose Utilization by Insulin
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Insulin stimulates the activity of mitogen-activated protein kinase (MAPK) via its upstream activator, MAPK kinase (MEK), a dual specificity kinase that phosphorylates MAPK on threonine and tyrosine. The potential role of MAPK activation in insulin action was investigated with the specific MEK inhibitor PD98059. Insulin stimulation of MAPK activity in 3T3-L1 adipocytes (2.7-fold) and L6 myotubes (1.4-fold) was completely abolished by pretreatment of cells with the MEK inhibitor, as was the phosphorylation of MAPK and pp90Rsk, and the transcriptional activation of c-fos. Insulin receptor autophosphorylation on tyrosine residues and activation of phosphatidylinositol 3'-kinase were unaffected. Pretreatment of cells with PD98059 had no effect on basal and insulin-stimulated glucose uptake, lipogenesis, and glycogen synthesis. Glycogen synthase activity in extracts from 3T3-L1 adipocytes and L6 myotubes was increased 3-fold and 1.7-fold, respectively, by insulin. Pretreatment with 10 microM PD98059 was without effect. Similarly, the 2-fold activation of protein phosphatase 1 by insulin was insensitive to PD98059. These results indicate that stimulation of the MAPK pathway by insulin is not required for many of the metabolic activities of the hormone in cultured fat and muscle cells.
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Inhibition of the MAPK kinase pathway prevents insulin-stimulated cell growth but has no effect on insulin's metabolic actions.
“Inhibition of the MAPK kinase pathway prevents the stimulation of cell growth by insulin but has no effect on the metabolic actions of the hormone [147].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [147]
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- Authors
- Lazar, D. F., Wiese, R. J., Brady, M. J., Mastick, C. C., Waters, S. B., Yamauchi, K., Pessin, J. E., Cuatrecasas, P., & Saltiel, A. R.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Saltiel, Alan R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-09
- Volume
- 270
- Issue
- 35
- Pages
- 20801-20807
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2024942502
- Cited by
- 396
- References
- 61
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 7 · 2014: 3 · 2013: 9 · 2012: 8
- FWCI
- 14.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- insulin signaling, MAPK signaling, MEK inhibition, PD98059, glucose uptake, glycogen synthase, protein phosphatase 1, insulin receptor autophosphorylation, phosphatidylinositol 3-kinase, adipocytes, myotubes, lipogenesis
- MeSH terms
- Animals, Biological Transport, Enzyme Activation, Enzyme Inhibitors, Flavonoids, Glucose, Glycogen, Insulin, Kinetics, L Cells, Phosphorylation, Receptor, Insulin, Transcriptional Activation, 3T3 Cells, Proto-Oncogene Proteins c-fos, Genes, fos, Phosphotransferases (Alcohol Group Acceptor), Calcium-Calmodulin-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors, Mice
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