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

TGF beta binding to the TGF beta receptor (T beta R) activates R-Smad-dependent pathways, such as Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the TGF beta-T beta RII-T beta RI-Smad2/3 pathway is established; however, it is not known how TGF beta activates ERK1/2. We show here that although TGF beta 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 T beta RII, which are 7- to 18-fold higher in dermal cells than in epidermal cells. Reduction of T beta RII expression in dermal cells abolished TGF beta-stimulated ERK1/2 activation. Upregulation of T beta RII expression in epidermal cells to a similar level as that in dermal cells switched TGF beta-induced ERK1/2 inhibition to ERK1/2 activation. More intriguingly, in contrast to the equal importance of TbRII in mediating TGF beta signaling to both Smad2/3 and ERK1/2, knockdown of T beta RI/Alk5 blocked activation of only Smad2/3, not ERK1/2, in dermal cells. Similarly, expression of the constitutively activated T beta RI-TD kinase activated only Smad2/3 and not ERK1/2 in epidermal cells. This study provides an explanation for why TGF beta selectively activates ERK1/2 in certain cell types and direct evidence for T beta RI-independent T beta RII signaling to a R-Smad-independent pathway.