TβRI/Alk5-independent TβRII signaling to ERK1/2 in human skin cells according to distinct levels of TβRII expression

B Bandyopadhyay, A Han, J Dai, J Fan… - Journal of cell …, 2011 - journals.biologists.com
B Bandyopadhyay, A Han, J Dai, J Fan, Y Li, M Chen, DT Woodley, W Li
Journal of cell science, 2011journals.biologists.com
TGFβ binding to the TGFβ receptor (TβR) activates R-Smad-dependent pathways, such as
Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the
TGFβ–TβRII–TβRI–Smad2/3 pathway is established; however, it is not known how TGFβ
activates ERK1/2. We show here that although TGFβ equally activated Smad2/3 in all cells, it
selectively activated ERK1/2 in dermal cells and inhibited ERK1/2 in epidermal cells. These
opposite effects correlated with the distinct expression levels of TβRII, which are 7-to 18-fold …
TGFβ binding to the TGFβ receptor (TβR) activates R-Smad-dependent pathways, such as Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the TGFβ–TβRII–TβRI–Smad2/3 pathway is established; however, it is not known how TGFβ activates ERK1/2. We show here that although TGFβ equally activated Smad2/3 in all cells, it selectively activated ERK1/2 in dermal cells and inhibited ERK1/2 in epidermal cells. These opposite effects correlated with the distinct expression levels of TβRII, which are 7- to 18-fold higher in dermal cells than in epidermal cells. Reduction of TβRII expression in dermal cells abolished TGFβ-stimulated ERK1/2 activation. Upregulation of TβRII expression in epidermal cells to a similar level as that in dermal cells switched TGFβ-induced ERK1/2 inhibition to ERK1/2 activation. More intriguingly, in contrast to the equal importance of TβRII in mediating TGFβ signaling to both Smad2/3 and ERK1/2, knockdown of TβRI/Alk5 blocked activation of only Smad2/3, not ERK1/2, in dermal cells. Similarly, expression of the constitutively activated TβRI-TD kinase activated only Smad2/3 and not ERK1/2 in epidermal cells. This study provides an explanation for why TGFβ selectively activates ERK1/2 in certain cell types and direct evidence for TβRI-independent TβRII signaling to a R-Smad-independent pathway.
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