title: Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport.
abstract: The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Although skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor, is essential for normal skin cell physiology. To identify the role of IRS-2 in skin cells, we studied cells isolated from IRS-2 knock-out (KO) mice. Whereas proliferation and differentiation were not affected in the IRS-2 KO cells, a striking effect was observed on glucose transport. In IRS-2 KO keratinocytes, the lack of IRS-2 resulted in a dramatic increase in basal and insulin-stimulated glucose transport. The increase in glucose transport was associated with an increase in total phosphatidylinositol (PI) 3-kinase and Akt activation. In contrast, fibroblasts lacking IRS-2 exhibited a significant decrease in basal and insulin-induced glucose transport. We identified the point of divergence, leading to these differences between keratinocytes and fibroblasts, at the IRS-PI 3-kinase association step. In epidermal keratinocytes, PI 3-kinase is associated with and activated by only the IRS-1 protein. On the other hand, in dermal fibroblasts, PI 3-kinase is exclusively associated with and activated by the IRS-2 protein. These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. Our results also show that IRS-2 function depends on its cell-specific association with PI 3-kinase.
authors.affiliation: Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sadagurski
authors.forename: Galina
authors.initials: G
authors.lastname: Weingarten
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Efrat
authors.initials: E
authors.lastname: Wertheimer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D003847:Deoxyglucose / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D006720:Homozygote; D015151:Immunoblotting; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D012867:Skin / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
chemical_list: D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D013936:Thymidine