This Article Full Text Full Text (PDF) Supplemental Data 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Google Scholar Articles by Sacco, A. Articles by Belfiore, A. PubMed PubMed Citation Articles by Sacco, A. Articles by Belfiore, A.

Differential Signaling Activation by Insulin and Insulin-Like Growth Factors I and II upon Binding to Insulin Receptor Isoform A

Endocrinology Unit (A.S., A.M., A.B.), Department of Clinical and Experimental Medicine, University of Catanzaro, 88100 Catanzaro, Italy; and Endocrinology Unit (G.P., R.V.), Department of Internal Medicine and Medical Specialties, University of Catania, Catania 95100, Italy

Address all correspondence and requests for reprints to: Antonino Belfiore, Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catanzaro, Campus Universitario, località, Germaneto, viale Europa, 88100 Catanzaro, Italy. E-mail: belfiore{at}unicz.it.

A variety of human malignancies overexpresses isoform A of the insulin receptor (IR-A) and produces IGFs (IGF-I and/or IGF-II). IR-A binds IGF-II with high affinity (although 4-fold lower than that for insulin), whereas it binds IGF-I with low affinity (approximately 30-fold lower than that for insulin). However, in engineered cells expressing only the IR-A, but not IGF-I receptor (R^–/IR-A cells), IGF-II is a more potent mitogen than insulin. Herein, we investigated downstream signaling of IGF-II, IGF-I, and insulin in R^–/IR-A cells to better understand their role in cell growth. We found that despite inducing a lower IR-A autophosphorylation than insulin, IGF-II was more potent than insulin for activating p70S6 kinase (p70S6K) and approximately equally potent in activating the early peaks of ERK1/2 and Akt. However, ERK1/2 activation persisted longer after IGF-II, whereas Akt activation persisted longer after insulin. Therefore, cells stimulated with IGF-II had a higher p70S6K/Akt activation ratio than cells stimulated with insulin. Remarkably, IGF-I also elicited a similar signaling pattern as IGF-II, despite inducing minimal IR-A autophosphorylation. ERK1/2 and protein kinase C seem to be involved in the preferential stimulation of p70S6K by IGFs. In conclusion, our study has identified a novel complex role of IR-A, which not only elicits a unique signaling pattern after IGF-II binding but also induces substantial downstream signaling upon binding to the low-affinity ligand IGF-I. These results underline the role of IR-A in physiology and disease.

This article has been cited by other articles:

				A. Belfiore, F. Frasca, G. Pandini, L. Sciacca, and R. Vigneri Insulin Receptor Isoforms and Insulin Receptor/Insulin-Like Growth Factor Receptor Hybrids in Physiology and Disease Endocr. Rev., October 1, 2009; 30(6): 586 - 623. [Abstract] [Full Text] [PDF]