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

Abstract

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.

Signaling Receptors for TGF-β Family Members

“…A possible explanation for the different efficiency in TGF-b-induced Erk1/2 MAP kinase activation came from the study of TGF-b signaling in dermal versus epidermal cells. In dermal cells, where TbRII levels are high, TGFb efficiently activated Erk1/2, whereas in epidermal cells with low levels of TbRII, Erk1/2 activation was actually inhibited; artificial expression of TbRII in epidermal cells switched these cells to Erk1/2 activation in response to TGF-b stimulation (Bandyopadhyay et al 2011). In this study, activation of Erk1/2 MAP kinase was found to be TbRI-independent.…”

Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

“…Indeed, moesin was reported to interact with Rab11 and rescues defects associated with Rab11 deficiency, which may be a mechanism by which moesin could promote recycling of the TGF-β receptors (43). Our study focused on TβRII since TGF-β signaling can occur via TβRII independently of TβRI activation (44). Studies with cyclohexamide or BFA confirmed disruption in the stability of surface TβRII in moesin-deficient cells.…”

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…The mechanism of the TGF-b-TbRII-TbRI-Smad2/3 pathway has been well-established. TbRI knockout or TbRI inhibitortreated cells will block TGF-b-induced phosphorylation of Smad2, which means without TbRI only TbRII cannot induce the activation of TGF-b signaling [50,51]. Moreover, it was proofed that TGF receptor type I:type II ratio has an important role in the activation of TGF-b signaling and expression of TGF-b-induced genes [52].…”