Transforming Growth Factor (TGF-β)-specific Signaling by Chimeric TGF-β Type II Receptor with Intracellular Domain of Activin Type IIB Receptor

Abstract Members of the transforming growth factor-β (TGF-β) superfamily signal via different heteromeric complexes of two sequentially acting serine/threonine kinase receptors, i.e.type I and type II receptors. We generated two different chimeric TGF-β superfamily receptors, i.e. TβR-I/BMPR-IB, containing the extracellular domain of TGF-β type I receptor (TβR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TβR-II/ActR-IIB, containing the extracellular domain of TGF-β type II receptor (TβR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB). In the presence of TGF-β1, TβR-I/BMPR-IB and TβR-II/ActR-IIB formed heteromeric complexes with wild-type TβR-II and TβR-I, respectively, upon stable transfection in mink lung epithelial cell lines. We show that TβR-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TβR-II with respect to TGF-β-mediated activation of a transcriptional signal, extracellular matrix formation, growth inhibition, and Smad phosphorylation. Moreover, TβR-I/BMPR-IB and TβR-II/ActR-IIB formed a functional complex in response to TGF-β and induced phosphorylation of Smad1. However, complex formation is not enough for signal propagation, which is shown by the inability of TβR-I/BMPR-IB to restore responsiveness to TGF-β in cell lines deficient in functional TβR-I. The fact that the TGF-β1-induced complex between TβR-II/ActR-IIB and TβR-I stimulated endogenous Smad2 phosphorylation, a TGF-β-like response, is in agreement with the current model for receptor activation in which the type I receptor determines signal specificity.