Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation.
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.
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Marianna
M
Sadagurski
Shoshana
S
Yakar
Galina
G
Weingarten
Martin
M
Holzenberger
Christopher J
CJ
Rhodes
Dirk
D
Breitkreutz
Derek
D
Leroith
Efrat
E
Wertheimer
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D018920:Coculture Techniques; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology* / Q000254:growth & development*; D058570:TOR Serine-Threonine Kinases
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C546843:mTOR protein, mouse