Distinct roles of the intracellular domains of transforming growth factor-beta type I and type II receptors in signal transduction.

Transforming growth factor-beta (TGF-beta) transduces signals through binding to type I (T beta R-I) and type II (T beta R-II) serine/threonine kinase receptors. T beta R-I requires T beta R-II for ligand binding, whereas T beta R-II requires T beta R-I for signaling. We generated two different chimeric TGF-beta receptors, i.e. T beta R-1.2 containing the extracellular domain of T beta R-I and the intracellular domain of T beta R-II, and T beta R-2.1 containing the extracellular domain of T beta R-II and the intracellular domain of T beta R-I. T beta R-2.1 bound 125I-TGF-beta 1 alone, whereas T beta R-1.2 bound the ligand only in the presence of T beta R-II or T beta R-2.1. When transfected into a mutant mink lung epithelial cell line that lacks functional T beta R-II, T beta R-II cDNA, but not T beta R-2.1 cDNA, restored the responsiveness to TGF-beta 1 with regard to transcriptional activation of plasminogen activator inhibitor-1 gene promoter and 12-O-tetradecanoylphorbol-13-acetate-responsive elements. In a mutant mink lung epithelial cell line lacking T beta R-I, T beta R-I cDNA stimulated promoter activity, but the T beta R-1.2 cDNA did not. T beta R-2.1 formed an oligomer with T beta R-II when transfected into COS cells, but the complex did not transduce the signal after ligand stimulation. On the other hand, co-transfection of T beta R-1.2 and T beta R-2.1 cDNAs restored the responsiveness to TGF-beta 1. These results indicate that an interaction between the intracellular regions of T beta R-I and T beta R-II, triggered by ligand binding to the extracellular domains of these receptors, leads to efficient signal transduction by TGF-beta.