A soluble transforming growth factor-β (TGF-β) type I receptor mimics TGF-β responses

Transforming growth factor-beta (TGF-beta) signaling requires a ligand-dependent interaction of TGF-beta receptors T betaR-I and T betaR-II. It has been previously demonstrated that a soluble TGF-beta type II receptor could be used as a TGF-beta antagonist. Here we have generated and investigated the biochemical and signaling properties of a soluble TGF-beta type I receptor (T beta RIs-Fc). As reported for the wild-type receptor, the soluble T betaR-I does not bind TGF-beta1 on its own. Surprisingly, in the absence of TGF-beta1, the T beta RIs-Fc mimicked TGF-beta1-induced transcriptional and growth responses in mink lung epithelial cells (Mv1Lu). Signaling induced by the soluble TGF-beta type I receptor is mediated via the obligatory presence of both TGF-beta type I and type II receptors at the cell surface since no signal was observed in Mv1Lu-derivated mutants for TGF-beta receptors R-1B and DR-26. The comparison between the structures of TGF-betas and a three-dimensional model of the extracellular domain of T beta RI has shown that five residues of the supposed binding site of TGF-beta1 (Lys(31), His(34), Glu(5), Tyr(91), and Lys(94)) were found with equivalent biochemical properties and similar spatial positions.