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J. Biol. Chem., Vol. 282, Issue 48, 35179-35186, November 30, 2007

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Activation of the Insulin Receptor by Insulin and a Synthetic Peptide Leads to Divergent Metabolic and Mitogenic Signaling and Responses^*

Maja Jensen¹, Bente Hansen, Pierre De Meyts, Lauge Schäffer^¶, and Birgitte Ursø

From the Receptor Systems Biology Laboratory, Hagedorn Research Institute, 2820 Gentofte, Denmark, the Department of Cancer and ImmunoBiology, Novo Nordisk, 2760 Maaloev, Denmark, and the ^¶Diabetes Protein Engineering, Novo Nordisk A/S, 2760 Maaloev, Denmark

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/ 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.

Received for publication, June 5, 2007 , and in revised form, September 4, 2007.

^* This work was supported by Novo Nordisk A/S. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. A-H.

¹ Recipient of an Industrial PhD scholarship from the Danish Ministry of Science, Technology and Innovation. To whom correspondence should be addressed: The Receptor Systems Biology Laboratory, Hagedorn Research Institute, Niels Steensensvej 6, 2820 Gentofte, Denmark. Tel.: 4544439078; Fax: 4544438000; E-mail: mjjn{at}novonordisk.com.

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