Figure 6.

Proposed model of TβR signaling pathway in normal human keratinocytes and squamous carcinoma cells. In normal human keratinocytes (exemplified by HaCaT cells), TGFβ binds to the TβRII and activates the classic Smad2/3 pathway via TβRI (Alk-5). In addition, our studies indicate that TGFβ can activate BMP-Smads (Smad1 and Smad5) in a TβRI (Alk-5)-dependent manner. In analogy with endothelial cells, we assume that one of the BMP type I receptors is involved in this process (Alk-x), with Alk-2 being the leading candidate. Moreover, one might speculate that the Smad2/3 arm of the signaling pathway mediates the homeostatic function of TGFβ, whereas the Smad1/5 arm is involved in the tissue injury response. In the case of some cancer-associated TβRII mutants (exemplified by TβRII^E526Q in SqCC/Y1 cells), both arms of the TGFβ/Smad pathway are abrogated. In contrast, in the case of TβRII^R537P-mutant A253 cells, the TβRII/Alk-5/Smad2/3 pathway is also abrogated, resulting in loss of TGFβ-mediated growth control. However, the Smad1/5 pathway is constitutively activated in an Alk-5-independent manner, apparently resulting in increased EMT, cell migration, and invasion. Thus, this type of mutant has a dual-function phenotype, associated with loss of one arm of the TGFβ/Smad pathway and activation of the second arm. Moreover, our studies indicate that this gain of function is inhibitable by the dual-receptor kinase inhibitor LY2109761, while it is resistant to selective TβRI kinase inhibitors.