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PMID:17925406

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Citation

Jensen, M, Hansen, B, De Meyts, P, Schäffer, L and Ursø, B (2007) Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses. J. Biol. Chem. 282:35179-86

Abstract

Recently, single chain peptides have been designed that target the insulin receptor and mimic insulin action. The aim of this study is to explore if activation of the insulin receptor with such an optimized peptide (S597) leads to the same activation of signaling pathways and biological endpoints i.e. stimulation of glycogen synthesis and cell proliferation as stimulation with insulin. We find that surface activation of the insulin receptor A-isoform with S597 leads to activation of protein kinase B (PKB) and glycogen synthesis comparable to activation by insulin, even though the level of insulin receptor phosphorylation is lower. In contrast, both Src homology 2/alpha collagen-related (Shc) and extracellular signal-regulated kinase (ERK) 2 activation are virtually absent upon stimulation with S597. Cell proliferation is only stimulated slightly by S597, suggesting that it depends on signals from Shc and ERK. The differences in signaling response could explain both the earlier reported differences in gene expression, and the reported differences in cell proliferation and glycogen synthesis induced by insulin and S597. In conclusion, despite binding equipotency, insulin, and S597 initiate different signaling and biological responses through the same insulin receptor isoform. We show for the first time that it is possible to design insulin receptor ligand mimetics with metabolic equipotency but low mitogenicity.

Links

PubMed Online version:10.1074/jbc.M704599200

Keywords

Animals; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases/metabolism; Gene Expression Regulation; Humans; Insulin/metabolism; Ligands; Models, Biological; Phosphorylation; Protein Isoforms; Rats; Receptor, Insulin/chemistry; Receptor, Insulin/metabolism; Signal Transduction; Time Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:O70360

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:P97880

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INSR

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INSR

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SHC1

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS1

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INS

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INS

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0045725: positive regulation of glycogen biosynthetic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IRS2

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

RAT:IRS1

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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