PMID:17925406

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
edit table

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

References

See Help:References for how to manage references in GONUTS.