Modulation of Insulin Receptor Substrate-1 Tyrosine Phosphorylation and Function by Mitogen-activated Protein Kinase
Open accessAbstract
Increased serine phosphorylation of insulin receptor substrate-1 (IRS-1) has been observed in several systems to correlate with a decreased ability of the insulin receptor to tyrosine-phosphorylate this endogenous substrate and to inhibit its subsequent association with phosphatidylinositol 3-kinase. In the present studies we have examined the potential role of the mitogen-activated protein (MAP) kinase in the increased serine phosphorylation of IRS-1 observed in human embryonic kidney cells treated with an activator of protein kinase C, phorbol 12-myristate 13-acetate. First, recombinantly produced kinase was shown to phosphorylate intact IRS-1 in a way that decreased the ability of isolated insulin receptor to phosphorylate the tyrosines recognized by the SH2 domains of the phosphatidylinositol 3-kinase. Second, an inhibitor of MAP kinase activation, PD98059, blocked the phorbol 12-myristate 13-acetate-induced inhibition of the insulin-stimulated increase in IRS-1 associated phosphatidylinositol 3-kinase. Third, activation of MAP kinase in intact cells via a regulatable upstream kinase, a RAF:estrogen receptor construct, could also inhibit the insulin-stimulated increase in IRS-1-associated phosphatidylinositol 3-kinase. Fourth, an in gel kinase assay showed that MAP kinase was the primary renaturable kinase in cell extracts capable of phosphorylating an IRS-1 fusion protein. Finally, IRS-1 was found to associate in coprecipitation studies with endogenous MAP kinase. These studies implicate MAP kinase as one of the kinases capable of phosphorylating and regulating IRS-1 tyrosine phosphorylation.
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Activation of these protein kinases phosphorylates IRS-1 at serine residue(s), which further interrupts tyrosine phosphorylation on IRS-1 and suppresses downstream insulin signaling.
“Other studies demonstrated that activation of these protein kinases phosphorylates IRS-1 at its serine residue(s), which further interrupts tyrosine phosphorylation on IRS-1 and suppresses downstream insulin signaling (12).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [12]
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- Authors
- De Fea, K., & Roth, R. A.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Roth, Richard A.
- ORCID
- Roth, Richard A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-12
- Volume
- 272
- Issue
- 50
- Pages
- 31400-31406
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2147825853
- Cited by
- 298
- References
- 36
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 9 · 2014: 10 · 2013: 4 · 2012: 9
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f32dk009310-01, DK 34926)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK34926, DK09310)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- IRS-1, serine phosphorylation, tyrosine phosphorylation, mitogen-activated protein kinase, phosphatidylinositol 3-kinase, insulin receptor, phorbol myristate acetate, protein kinase C, PD98059, SH2 domain, insulin signaling
- MeSH terms
- Animals, Enzyme Activation, Cricetinae, Humans, Kidney, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Recombinant Proteins, Serine, Tetradecanoylphorbol Acetate, Tyrosine, CHO Cells, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinase 3, MAP Kinase Kinase 1, Insulin Receptor Substrate Proteins
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