Although transforming growth factor- (TGF) is implicated in differentiation and disease, proof of in vivo function requires specific inhibitors of the TGF cascade. TGF binds a family of type I and type II receptors (TRI, TRII), containing a cytoplasmic serine/threonine kinase domain. We previously reported that kinase-deficient TRII (kTRII) blocks TGF-dependent transcription in cardiac myocytes. It is controversial whether both receptors are needed in all cells for gene regulation by TGF or whether they mediate distinct subsets of TGF-dependent events. To resolve this uncertainty, TGF-dependent transcription was investigated in cardiac myocytes versus mink lung epithelial cells. 1) kTRII inhibits induction of a TGF-responsive reporter gene, in both cell backgrounds. 2) Charged-to-alanine mutations of key residues of the TRII kinase, including consensus ATP binding and amino acid recognition motifs, are competent for binding but not transcriptional activation. Each inactive receptor inhibits TGF-dependent transcription in both cell types. 3) Kinase-deficient TRI (kTRI) likewise impairs TGF-dependent transcription, less completely than kTRII; kinase-deficient activin type I receptor has no effect. 4) TGF-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 TRII and TRI. Thus, the model inferred from TGF-resistant cell lines (that TRII and TRI are necessary in tandem for the TGF-signaling complex to regulate transcription) is valid for cardiac myocytes, the cell type most prominently affected in TGF-deficient animals.

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