Inactive type II and type I receptors for TGF beta are dominant inhibitors of TGF beta-dependent transcription.
Although transforming growth factor-beta (TGF beta) is implicated in differentiation and disease, proof of in vivo function requires specific inhibitors of the TGF beta cascade. TGF beta binds a family of type I and type II receptors (T beta RI, T beta RII), containing a cytoplasmic serine/threonine kinase domain. We previously reported that kinase-deficient T beta RII (delta kT beta RII) blocks TGF beta-dependent transcription in cardiac myocytes. It is controversial whether both receptors are needed in all cells for gene regulation by TGF beta or whether they mediate distinct subsets of TGF beta-dependent events. To resolve this uncertainty, TGF beta-dependent transcription was investigated in cardiac myocytes versus mink lung epithelial cells. 1) delta kT beta RII inhibits induction of a TGF beta-responsive reporter gene, in both cell backgrounds. 2) Charged-to-alanine mutations of key residues of the T beta RII kinase, including consensus ATP binding and amino acid recognition motifs, are competent for binding but not transcriptional activation. Each inactive receptor inhibits TGF beta-dependent transcription in both cell types. 3) Kinase-deficient T beta RI (delta kT beta RI) likewise impairs TGF beta-dependent transcription, less completely than delta kT beta RII; kinase-deficient activin type I receptor has no effect. 4) TGF beta-binding proteins in cardiac cells and Mv1Lu cells are comparable by affinity labeling and immunoprecipitation; however, Mv1Lu cells express up to 3-fold higher levels of T beta RII and T beta RI. Thus, the model inferred from TGF beta-resistant cell lines (that T beta RII and T beta RI are necessary in tandem for the TGF beta-signaling complex to regulate transcription) is valid for cardiac myocytes, the cell type most prominently affected in TGF beta-deficient animals.
Brand
T
T
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Schneider
M D
MD
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D008907:Mink; D008969:Molecular Sequence Data; D010641:Phenotype; D010770:Phosphotransferases / Q000172:deficiency; D017354:Point Mutation; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000502:physiology*
D018125:Receptors, Transforming Growth Factor beta; D010770:Phosphotransferases