title: Ganglioside GM3 Mediates Glucose-Induced Suppression of IGF-1 Receptor-Rac1 Activation to Inhibit Keratinocyte Motility.
abstract: Activation of insulin-like growth factor-1 (IGF-1) receptor (IGF1R) signaling induces keratinocyte migration, but little is known about its regulation, including in diabetic wounds. GM3, a lipid raft ganglioside synthesized by GM3 synthase (GM3S), regulates receptor signaling. In diabetic mice, knockout or topically applied nanoconstruct-mediated knockdown of GM3S promotes wound edge IGF1R phosphorylation and re-epithelialization. Through modulating GM3 expression, we explored the role of GM3 in regulating human keratinocyte IGF1R signaling. Increases in GM3 and GM3S expression, including by exposure to high glucose, inhibit keratinocyte migration and IGF-1-induced chemotaxis in association with inhibition of IGF1R phosphorylation, suppression of Rac1 signaling, and activation of RhoA signaling. In contrast, GM3 depletion accelerates cell migration; increases cell velocity, displacement, and persistence; and activates IGF1R-Rac1 signaling. These data implicate GM3 in mediating glucose-induced suppression of IGF1R-Rac1 signaling. Furthermore, our findings provide evidence of a pivotal role for GM3-induced insulin resistance in impairing keratinocyte migration and reinforce the previously published studies in diabetic mice supporting GM3-depleting strategies as an approach for accelerating the healing of human diabetic wounds.
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Duncan Hieu M
authors.initials: DHM
authors.lastname: Dam
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sheu
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Mahima
authors.initials: M
authors.lastname: Vijay
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Desmond
authors.initials: D
authors.lastname: Shipp
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Miller
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: apaller@northwestern.edu.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
mesh_terms: D002465:Cell Movement; D017719:Diabetic Foot / Q000378:metabolism; D005679:G(M3) Ganglioside / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D015603:Keratinocytes / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D005679:G(M3) Ganglioside; C107953:RAC1 protein, human; D017526:Receptor, IGF Type 1; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D005947:Glucose