Editors' ChoiceCell Biology

TSC1 strikes out on its own

Sci. Signal.  24 Mar 2015:
Vol. 8, Issue 369, pp. ec66
DOI: 10.1126/scisignal.aab1622

Heterodimers of tuberous sclerosis 1 and 2 (TSC1 and TSC2) inhibit signaling through the mechanistic target of rapamycin complex 1 (mTORC1), thus reducing cell growth and proliferation. Thien et al. found that TSC1 functions independently of TSC2 and mTORC1 to promote transforming growth factor–β (TGF-β) signaling. Following their phosphorylation by the activated TGF-β receptor complex, Smad2 and Smad3 bind to Smad4 and translocate into the nucleus where they directly regulate gene expression to elicit various responses, such as growth arrest and epithelial-to-mesenchymal transition (EMT). In HeLa cells, knocking down TSC1, but not TSC2, by RNA interference reduced phosphorylation and nuclear translocation of Smad2 and Smad3 and reduced expression of one of their target genes in response to stimulation with the ligand TGF-β1, but did not inhibit BMP (bone morphogenetic protein)-mediated signaling by Smads1, 5, and 8. Inhibiting mTORC1 signaling by several different methods did not affect TGF-β1–induced phosphorylation of Smad2 and Smad3. Proximity ligation assays and coimmunoprecipitation experiments showed that TSC1 formed a complex with Smad2, Smad3, and the TGF-β receptor TβR-I upon TGF-β stimulation. TSC1 enhanced the association of Smad2 and Smad3 with TβR-I in response to TGF-β1. The kinase Akt inhibits the TSC1-TSC2 complex downstream of insulin and phosphoinositide 3–kinase (PI3K) by phosphorylating TSC2 to disrupt the TSC1-TSC2 complex. Expression of a constitutively activated form of Akt stimulated TβR-I–dependent phosphorylation of Smad2 and Smad3 and promoted the association of TSC1 with TβR-I, Smad2, and Smad3. Insulin also stimulated TGF-β1–induced phosphorylation of Smad2 and Smad3, and the PI3K signaling antagonist PTEN inhibited TGF-β1–induced phosphorylation of Smad2 and Smad3. Thus, although Akt inhibits the ability of the TSC1-TSC2 complex to suppress mTORC1 signaling, it stimulates the ability of TSC1 to promote TGF-β signaling. In cultured mouse cells treated with TGF-β1, efficient growth arrest and Smad4-dependent morphological changes characteristic of EMT required TSC1. Cells expressing constitutively active Akt arrested cell proliferation, failed to stimulate EMT, in response to TGF-β1, likely because Akt has additional targets that control EMT. These findings functionally link insulin-PI3K-Akt signaling to the TGF-β pathway and have important ramifications for cancer treatments that target the PI3K-Akt axis. Drugs that reduce Akt activity might have the unwanted side effect of reducing TGF-β signaling–dependent growth arrest.

A. Thien, M. T. Prentzell, B. Holzwarth, K. Kläsener, I. Kuper, C. Boehlke, A. G. Sonntag, S. Ruf, L. Maerz, R. Nitschke, S. -N. Grellscheid, M. Reth, G. Walz, R. Baumeister, E. Neumann-Haefelin, K. Thedieck, TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition. Dev. Cell. 32, 617–630 (2015). [PubMed]

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