TRANSFORMING-GROWTH-FACTOR (TGF-BETA)-SPECIFIC SIGNALING BY CHIMERIC TGF-BETA TYPE-II RECEPTOR WITH INTRACELLULAR DOMAIN OF ACTIVIN TYPE IIB RECEPTOR

Members of the transforming growth factor-beta (TGF-beta) 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-beta superfamily receptors, i. e. T beta R-I/BMPR-IB, containing the extracellular domain of TGF-beta type I receptor (TPR-I) and the intracellular domain of bone morphoge netic protein type IB receptor (BMPR-IB), and T beta R-II/ActR-IIB, co ntaining the extracellular domain of TGF-beta type II receptor (TPR-II ) and the intracellular domain of activin type IIB receptor (ActR-IIB) , In the presence of TGF-beta 1, T beta R-I/BMPR-IB and T beta R-II/Ac tR-IIB formed heteromeric complexes with wild-type TPR-II and TPR-I, r espectively, upon stable transfection in mink lung epithelial cell lin es, We show that T beta R-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TPR II with resp ect to TGF-beta-mediated activation of a transcriptional signal, extra cellular matrix formation, growth inhibition, and Smad phosphorylation . Moreover, T beta R-I/BMPR-IB and T beta R-II/ActR-IIB formed a funct ional complex in response to TGF-beta and induced phosphorylation of S mad1, However, complex formation is not enough for signal propagation, which is shown by the inability of T beta R-I/BMPR-IB to restore resp onsive ness to TGF-beta in cell lines deficient in functional TPR-I, T he fact that the TGF-beta 1-induced complex between T beta R-II/ActR-I IB and TPR-I stimulated endogenous Smad2 phosphorylation, a TGF-beta-l ike response, is in agreement with the current model for receptor acti vation in which the type I receptor determines signal specificity.