Editors' ChoiceSignal Modulation

Shifting the Smad Balance

Science's STKE  09 Sep 2003:
Vol. 2003, Issue 199, pp. tw348-TW348
DOI: 10.1126/stke.2003.199.tw348

Transforming growth factor-β (TGF-β), a cytokine involved in cell growth and development, binds to type II receptors at the cell surface, which leads to the activation of type I receptors, and they phosphorylate the receptor-activated proteins Smad2 and Smad3. Phosphorylated Smad2 and Smad3 dissociate from the receptor and--after forming a complex with Smad4--translocate to the nucleus, where Smad2 and Smad3 activate the transcription of target genes. Felici et al. identified a new TGF-β receptor-associated protein, TLP [TGF-β receptor I-associated protein-1 (TRAP-1)-like protein], that, unlike previously identified Smad regulators, has opposing effects on Smad2- and Smad3-dependent signaling. The authors used immunoprecipitation and Western analysis in combination with the cotransfection of TLP and TGF-β superfamily receptors and receptor activation mutants to investigate the association of TLP with proteins involved in TGF-β signaling. Endogenous and overexpressed TLP associated with TGF-β and activin type II receptors, regardless of activation status. The association of endogenous TLP with Smad4, however, depended on TGF-β signaling. Although TLP did not affect Smad phosphorylation, TLP overexpression activated the transcription of Smad2-dependent gene reporters without affecting Smad2 association with Smad4, whereas TLP inhibited both Smad3-dependent transcription and the association of Smad3 with Smad4. Down-regulation of endogenous TLP expression with small-interfering RNA (siRNA) also inhibited TGF-β-stimulated Smad3-dependent signaling. The authors proposed that TLP acts as a molecular switch to regulate the balance between Smad2- and Smad3-mediated signaling after TGF-β stimulation and developed a model whereby this might occur.

A. Felici, J. U. Wurthner, W. T. Parks, L. R.-Y. Gian, M. Reiss, T. S. Karpova, J. G. McNally, A. B. Roberts, TLP, a novel modulator of TGF-β signaling, has opposite effects on Smad2- and Smad3-dependent signaling. EMBO J. 22, 4465-4477 (2003). [Abstract] [Full Text]