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. TbetaR-I/BMPR-IB, containing the extracellular domain of TGF-beta type I receptor (TbetaR-I) and the intracellular domain of bone morphogenetic protein type IB receptor (BMPR-IB), and TbetaR-II/ActR-IIB, containing the extracellular domain of TGF-beta type II receptor (TbetaR-II) and the intracellular domain of activin type IIB receptor (ActR-IIB). In the presence of TGF-beta1, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed heteromeric complexes with wild-type TbetaR-II and TbetaR-I, respectively, upon stable transfection in mink lung epithelial cell lines. We show that TbetaR-II/ActR-IIB restored the responsiveness upon transfection in mutant cell lines lacking functional TbetaR-II with respect to TGF-beta-mediated activation of a transcriptional signal, extracellular matrix formation, growth inhibition, and Smad phosphorylation. Moreover, TbetaR-I/BMPR-IB and TbetaR-II/ActR-IIB formed a functional complex in response to TGF-beta and induced phosphorylation of Smad1. However, complex formation is not enough for signal propagation, which is shown by the inability of TbetaR-I/BMPR-IB to restore responsiveness to TGF-beta in cell lines deficient in functional TbetaR-I. The fact that the TGF-beta1-induced complex between TbetaR-II/ActR-IIB and TbetaR-I stimulated endogenous Smad2 phosphorylation, a TGF-beta-like response, is in agreement with the current model for receptor activation in which the type I receptor determines signal specificity.
Persson
U
U
Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden. Urban.Persson@LICR.uu.se
Souchelnytskyi
S
S
Franzén
P
P
Miyazono
K
K
ten Dijke
P
P
Heldin
C H
CH
D029404:Activin Receptors; D030201:Activin Receptors, Type I; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017978:Receptors, Growth Factor / Q000737:chemistry / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D015398:Signal Transduction; D051899:Smad2 Protein; D051902:Smad5 Protein; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D008024:Ligands; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D030201:Activin Receptors, Type I; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II