Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation

Marianna Sadagurski, Shoshana Yakar, Galina Weingarten, Martin Holzenberger, Christopher J. Rhodes, Dirk Breitkreutz, Derek LeRoith, Efrat Wertheimer

Research output: Contribution to journalArticle

Abstract

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-1M-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) overespression 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.

Original languageEnglish (US)
Pages (from-to)2675-2687
Number of pages13
JournalMolecular and Cellular Biology
Volume26
Issue number7
DOIs
StatePublished - Apr 2006

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Somatomedin Receptors
Keratinocytes
Skin
Phosphatidylinositol 3-Kinase
Insulin Receptor Substrate Proteins
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Sirolimus
Coculture Techniques
Electric Impedance
Epidermis
Cell Differentiation
Cell Survival
Cell Proliferation
Parturition

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. / Sadagurski, Marianna; Yakar, Shoshana; Weingarten, Galina; Holzenberger, Martin; Rhodes, Christopher J.; Breitkreutz, Dirk; LeRoith, Derek; Wertheimer, Efrat.

In: Molecular and Cellular Biology, Vol. 26, No. 7, 04.2006, p. 2675-2687.

Research output: Contribution to journalArticle

Sadagurski, M, Yakar, S, Weingarten, G, Holzenberger, M, Rhodes, CJ, Breitkreutz, D, LeRoith, D & Wertheimer, E 2006, 'Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation', Molecular and Cellular Biology, vol. 26, no. 7, pp. 2675-2687. https://doi.org/10.1128/MCB.26.7.2675-2687.2006
Sadagurski, Marianna ; Yakar, Shoshana ; Weingarten, Galina ; Holzenberger, Martin ; Rhodes, Christopher J. ; Breitkreutz, Dirk ; LeRoith, Derek ; Wertheimer, Efrat. / Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 7. pp. 2675-2687.
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