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J. Biol. Chem., Vol. 277, Issue 39, 36045-36051, September 27, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/39/36045    most recent M200575200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gogg, S. Articles by Smith, U. Search for Related Content PubMed PubMed Citation Articles by Gogg, S. Articles by Smith, U. Social Bookmarking                      What's this?

Epidermal Growth Factor and Transforming Growth Factor  Mimic the Effects of Insulin in Human Fat Cells and Augment Downstream Signaling in Insulin Resistance^*

Silvia Gogg and Ulf Smith

From the Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, the Sahlgrenska Academy at Göteborg University, SE-413 45 Göteborg, Sweden

The ability of the growth factors epidermal growth factor (EGF), transforming growth factor , and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. No effects were found in rat fat cells, whereas EGF (EC₅₀ for glucose transport ~0.02 nM) and transforming growth factor  (EC₅₀ ~0.2 nM), but not platelet-derived growth factor, mimicked the effects of insulin (EC₅₀ ~0.2 nM) on both pathways. EGF receptors, but not EGF, were abundantly expressed in human fat cells as well as in human skeletal muscle. EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. Thus, EGF receptors, but not EGF, are abundantly expressed in human fat cells and skeletal muscle. EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes.

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