TSC1 activates TGF-?-smad2/3 signaling in growth arrest and epithelial-to-mesenchymal rransition
26.02.2015
Thien A, Prentzell MT, Holzwarth B, Kläsener K, Kuper I, Boehlke C, Sonntag AG, Ruf S, Maerz L, Nitschke R, Grellscheid SN, Reth M, Walz G, Baumeister R, Neumann-Haefelin E, Thedieck K.
Dev Cell. 2015 Mar 9;32(5):617-30.
The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling. They suppress cell growth and proliferation by acting in a heteromeric complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1). In this study, we identify TSC1 as a component of the transforming growth factor b (TGF-b)-Smad2/3 pathway. Here, TSC1 functions independently of TSC2. TSC1 interacts with the TGF-b receptor complex and Smad2/3 and is required for their association with one another. TSC1 regulates TGF-b-induced Smad2/3 phosphorylation and target gene expression and controls TGFb- induced growth arrest and epithelial-to-mesenchymal transition (EMT). Hyperactive Akt specifically activates TSC1-dependent cytostatic Smad signaling to induce growth arrest. Thus, TSC1 couples Akt activity to TGF-b-Smad2/3 signaling. This has implications for cancer treatments targeting phosphoinositide 3-kinases and Akt because they may impair tumor-suppressive cytostatic TGF-b signaling by inhibiting Akt- and TSC1-dependent Smad activation.
