ArticleThe Journal of biological chemistry2013
Phosphorylation of serine 1137/1138 of mouse insulin receptor substrate (IRS) 2 regulates cAMP-dependent binding to 14-3-3 proteins and IRS2 protein degradation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways.Current issues in molecular biology · 2024Review
- Is 14-3-3 the Combination to Unlock New Pathways to Improve Metabolic Homeostasis and β-Cell Function?Diabetes · 2023Review
- The Integration of Proteome-Wide PTM Data with Protein Structural and Sequence Features Identifies Phosphorylations that Mediate 14-3-3 Interactions.Journal of molecular biology · 2023Article
- 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing.Science advances · 2022Article
- Interrogating Kinase-Substrate Relationships with Proximity Labeling and Phosphorylation Enrichment.Journal of proteome research · 2022Article
- Article
- Etiology of Metabolic Syndrome and Dietary Intervention.International journal of molecular sciences · 2018Review
- Scaffold Proteins: From Coordinating Signaling Pathways to Metabolic Regulation.Endocrinology · 2018Review
- Review
- The impact of insulin resistance on the kidney and vasculature.Nature reviews. Nephrology · 2016Review
- Article
- Changes in Brain 14-3-3 Proteins in Response to Insulin Resistance Induced by a High Palatable Diet.Molecular neurobiology · 2015Article
- 14-3-3ζ coordinates adipogenesis of visceral fat.Nature communications · 2015Article
- Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation.Biochemistry · 2015Article
- The Novel Functions of High-Molecular-Mass Complexes Containing Insulin Receptor Substrates in Mediation and Modulation of Insulin-Like Activities: Emerging Concept of Diverse Functions by IRS-Associated Proteins.Frontiers in endocrinology · 2015Review
- cAMP-dependent insulin modulation of synaptic inhibition in neurons of the dorsal motor nucleus of the vagus is altered in diabetic mice.American journal of physiology. Regulatory, integrative and comparative physiology · 2014Article
- 14-3-3-β and -{varepsilon} contribute to activation of the osmoprotective transcription factor NFAT5 by increasing its protein abundance and its transactivating activity.Physiological reports · 2014Article
- Article
- An endogenous PI3K interactome promoting astrocyte-mediated neuroprotection identifies a novel association with RNA-binding protein ZC3H14.The Journal of biological chemistryArticle
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insulin receptor substrate (IRS) 2 as intermediate docking platform transduces the insulin/IGF-1 (insulin like growth factor 1) signal to intracellular effector molecules that regulate glucose homeostasis, β-cell growth, and survival. Previously, IRS2 has been identified as a 14-3-3 interaction protein. 14-3-3 proteins can bind their target proteins via phosphorylated serine/threonine residues located within distinct motifs. In this study the binding of 14-3-3 to IRS2 upon stimulation with forskolin or the cAMP analog 8-(4-chlorophenylthio)-cAMP was demonstrated in HEK293 cells. Binding was reduced with PKA inhibitors H89 or Rp-8-Br-cAMPS. Phosphorylation of IRS2 on PKA consensus motifs was induced by forskolin and the PKA activator N(6)-Phe-cAMP and prevented by both PKA inhibitors. The amino acid region after position 952 on IRS2 was identified as the 14-3-3 binding region by GST-14-3-3 pulldown assays. Mass spectrometric analysis revealed serine 1137 and serine 1138 as cAMP-dependent, potential PKA phosphorylation sites. Mutation of serine 1137/1138 to alanine strongly reduced the cAMP-dependent 14-3-3 binding. Application of cycloheximide revealed that forskolin enhanced IRS2 protein stability in HEK293 cells stably expressing IRS2 as well as in primary hepatocytes. Stimulation with forskolin did not increase protein stability either in the presence of a 14-3-3 antagonist or in the double 1137/1138 alanine mutant. Thus the reduced IRS2 protein degradation was dependent on the interaction with 14-3-3 proteins and the presence of serine 1137/1138. We present serine 1137/1138 as novel cAMP-dependent phosphorylation sites on IRS2 and show their importance in 14-3-3 binding and IRS2 protein stability.
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