TY - JOUR
T1 - Ganglioside GM3 Mediates Glucose-Induced Suppression of IGF-1 Receptor–Rac1 Activation to Inhibit Keratinocyte Motility
AU - Dam, Duncan Hieu M.
AU - Wang, Xiao Qi
AU - Sheu, Sarah
AU - Vijay, Mahima
AU - Shipp, Desmond
AU - Miller, Luke
AU - Paller, Amy S.
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jid.2016.09.028
DO - 10.1016/j.jid.2016.09.028
M3 - Article
C2 - 27729281
AN - SCOPUS:85010376013
SN - 0022-202X
VL - 137
SP - 440
EP - 448
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -