Cited by 326Metabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancer

Expression and function of IRS-1 in insulin signal transmission.

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Sun, X.J., Miralpeix, M, Myers, M G, Glasheen, E.M., Backer, J.M., Kahn, C.R., White, M.F.·1992·Journal of Biological Chemistry

Abstract

IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. The mRNA for IRS-1 in rat cells and tissues is about 9.5 kilobases (kb). Rat liver IRS-1 was stably expressed in Chinese hamster ovary (CHO) cells (CHO/IRS-1). Although its calculated molecular mass is 131 kDa, IRS-1 from quiescent cells migrated between 165 and 170 kDa during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. Some IRS-1 associated with the insulin receptor during insulin stimulation. In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission.

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Crossref · 10.1016/s0021-9258(18)41723-1

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  • PI3K inhibitors impair glucose transport and block activation of glycogen synthase and HK-II expression.

    “Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [144]

  • Phosphorylated tyrosine residues of IRS-1 mediate association with the 85-kDa regulatory subunit of PI3K, activating the enzyme.

    “The phosphorylated tyrosine residues of IRS-1 mediate an association with the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to activation of the enzyme [138–140, 143, 144].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [144]

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Authors
Sun, X. J., Miralpeix, M., Myers, M. G., Glasheen, E. M., Backer, J. M., Kahn, C. R., & White, M. F.
Affiliations
Joslin Diabetes Center (US)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1992-11
Volume
267
Issue
31
Pages
22662-22672
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1524336750
Cited by
326
References
42
Citations by year
2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 9 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 11
FWCI
12.17
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK 33201, DK36836, DK 43808, R01DK033201, R01DK043808, P30DK036836)
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 › PI3K/AKT/mTOR signaling in cancer
Keywords
IRS-1, insulin signaling, insulin receptor, tyrosine phosphorylation, serine phosphorylation, phosphatidylinositol 3-kinase, subcellular localization, CHO cell expression
MeSH terms
Amino Acid Sequence, Animals, Cytoplasm, DNA, Cricetinae, Molecular Sequence Data, Phosphoproteins, Phosphorylation, Phosphotransferases, Protein-Tyrosine Kinases, Receptor, Insulin, Recombinant Proteins, RNA, Messenger, Tyrosine, Signal Transduction, Gene Expression, CHO Cells, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Rats, Insulin Receptor Substrate Proteins

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