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.
Okadome
T
T
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Yamashita
H
H
Franzén
P
P
Morén
A
A
Heldin
C H
CH
Miyazono
K
K
D000818:Animals; D002460:Cell Line; D006801:Humans; D008907:Mink; D011485:Protein Binding; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta