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Molecular and Cellular Biology, April 2006, p. 2675-2687, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2675-2687.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Insulin-Like Growth Factor 1 Receptor Signaling Regulates Skin Development and Inhibits Skin Keratinocyte Differentiation

Marianna Sadagurski,1 Shoshana Yakar,2 Galina Weingarten,1 Martin Holzenberger,3 Christopher J. Rhodes,4 Dirk Breitkreutz,5 Derek LeRoith,2 and Efrat Wertheimer1*

Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel,1 Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland,2 INSERM U515, Saint-Antoine Hospital, Paris, France,3 Pacific Northwest Research Institute, Seattle, Washington,4 German Cancer Research Center, Division A080, Heidelberg, Germany5

Received 15 September 2005/ Returned for modification 21 October 2005/ Accepted 22 December 2005

The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. However, because IGF-1R-null mice die at birth, it is difficult to study the effects of IGF-1R on skin. By using a combined approach of conditional gene ablation and a three-dimensional organotypic model, we demonstrate that IGF-1R-deficient skin cocultures show abnormal maturation and differentiation patterns. Furthermore, IGF-1R-null keratinocytes exhibit accelerated differentiation and decreased proliferation. Investigating the signaling pathway downstream of IGF-1R reveals that insulin receptor substrate 2 (IRS-2) overexpression compensates for the lack of IGF-1R, whereas IRS-1 overexpression does not. We also demonstrate that phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1 and 2 are involved in the regulation of skin keratinocyte differentiation and take some part in mediating the inhibitory signal of IGF-1R on differentiation. In addition, we show that mammalian target of rapamycin plays a specific role in mediating IGF-1R impedance of action on keratinocyte differentiation. In conclusion, these results reveal that IGF-1R plays an inhibitory role in the regulation of skin development and differentiation.

* Corresponding author. Mailing address: Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Phone: 972-3-640-6111. Fax: 972-3-640-9141. E-mail: effy{at}patholog.tau.ac.il.

Molecular and Cellular Biology, April 2006, p. 2675-2687, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2675-2687.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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