Lefty inhibits recepter-regulated smad phosphorylation induced by the activated transforming growth factor-beta receptor

Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine that r egulates growth and differentiation of diverse types of cells. TGF-beta act ions are directed by ligand-induced activation of TGF-beta receptors with i ntrinsic serine/threonine kinase activity that trigger phosphorylation of r eceptor-regulated Smad (R-Smad) protein. Phosphorylated R-Smad proteins bin d to Smad4, and the complexes formed move into the nucleus, where they act as components of a transcriptional complex. Here, we show that TGF-beta sig naling is inhibited by lefty, a novel member of the TGF-beta superfamily, L efty perturbed TGF-beta signaling by inhibiting the phosphorylation of Smad 2 following activation of the TGF-beta receptor. Moreover, lefty inhibited the events that lie downstream from R-Smad phosphorylation, including heter odimerization of R-Smad proteins with Smad4 and nuclear translocation of th e R-Smad Smad4 complex. Lefty repressed TGF-beta -induced expression of rep orter genes for the p21, cdc25, and connective tissue growth factor promote rs and of a reporter gene driven by the Smad-binding element. Similarly, le fty inhibited both BMP-mediated Smad5 phosphorylation and gene transcriptio n. The action of lefty does not appear to depend on protein synthesis, incl uding synthesis of inhibitory Smad proteins. Thus, lefty provides a repress ed state of TGF-beta- or BMP-responsive genes and participates in negative modulation of TGF-beta and BMP signaling by inhibition of phosphorylation o f R-Smad proteins.