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Adipose-specific Expression, Phosphorylation of Ser794 in Insulin Receptor Substrate-1, and Activation in Diabetic Animals of Salt-inducible Kinase-2
Open accessAbstract
Salt-inducible kinase (SIK), first cloned from the adrenal glands of rats fed a high salt diet, is a serine/threonine protein kinase belonging to an AMP-activated protein kinase family. Induced in Y1 cells at an early stage of ACTH stimulation, it regulated the initial steps of steroidogenesis. Here we report the identification of its isoform SIK2. When a green fluorescent protein-fused SIK2 was expressed in 3T3-L1 preadipocytes, it was mostly present in the cytoplasm. When coexpressed in cAMP-responsive element-reporter assay systems, SIK2 could repress the cAMP-responsive element-dependent transcription, although the degree of repression seemed weaker than that by SIK1. SIK2 was specifically expressed in adipose tissues. When 3T3-L1 cells were treated with the adipose differentiation mixture, SIK2 mRNA was induced within 1 h, the time of induction almost coinciding with that of c/EBPbeta mRNA. Coexpressed with human insulin receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser(794) of human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated the level of phosphorylation at Ser(789), the mouse equivalent of human Ser(794). Moreover, the activity and content of SIK2 were elevated in white adipose tissues of db/db diabetic mice. These results suggest that highly expressed SIK2 in insulin-stimulated adipocytes phosphorylates Ser(794) of IRS-1 and, as a result, might modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance in diabetic animals.
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“Alternative studies show that IRS1 S789 phosphorylation is negatively associated with insulin signaling [146-149].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [148]
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Metadata
- Authors
- Horike, N., Takemori, H., Katoh, Y., Doi, J., Min, L., Asano, T., Sun, X. J., Yamamoto, H., Kasayama, S., Muraoka, M., Nonaka, Y., & Okamoto, M.
- Affiliations
- The University of Osaka (JP)
- Senri Kinran University (JP)
- The University of Tokyo (JP)
- University of Vermont (US)
- Koshien University (JP)
- Corresponding author
- Okamoto, Mitsuhiro
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 278
- Issue
- 20
- Pages
- 18440-18447
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2168780144
- Cited by
- 161
- References
- 48
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 11 · 2022: 4 · 2021: 11 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 1 · 2016: 4 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 12
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Dartmouth College
- Uehara Memorial Foundation (CREST)
- Salt Science Research Foundation
- Japan Society for the Promotion of Science (CREST)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- SIK2, IRS-1, adipose tissue, adipogenesis, C/EBPβ, insulin resistance, type 2 diabetes, db/db mice, insulin signaling
- MeSH terms
- Cyclic AMP, Adipose Tissue, Amino Acid Sequence, Animals, Cell Differentiation, Cell Line, Cloning, Molecular, Escherichia coli, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Molecular Sequence Data, Phosphoproteins, Phosphorylation, Plasmids, Precipitin Tests, RNA, Messenger, Serine, Tissue Distribution, Blotting, Northern, 3T3 Cells, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Adipocytes, DNA, Complementary, COS Cells, Protein Isoforms, Mice, Insulin Receptor Substrate Proteins
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