Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor

• Published in: Molecular biology of the cell 2001-09, Vol.12 (9), p.2881-2893
• Main Authors: Garamszegi, N, Doré, Jr, J J, Penheiter, S G, Edens, M, Yao, D, Leof, E B
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Cell Line; DNA-Binding Proteins - metabolism; Down-Regulation; Endocytosis; Fibroblasts; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphorylation; Plasminogen Activator Inhibitor 1 - metabolism; Protein Structure, Tertiary; Receptors, Transforming Growth Factor beta - chemistry; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sequence Deletion; Signal Transduction; Smad2 Protein; Time Factors; Trans-Activators - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.12.9.2881

Transforming growth factor beta (TGF-beta) coordinates a number of biological events important in normal and pathophysiological growth. In this study, deletion and substitution mutations were used to identify receptor motifs modulating TGF-beta receptor activity. Initial experiments indicated that a COOH-terminal sequence between amino acids 482-491 in the kinase domain of the type I receptor was required for ligand-induced receptor signaling and down-regulation. These 10 amino acids are highly conserved in mammalian, Xenopus, and Drosophila type I receptors. Although mutation or deletion of the region (referred to as the NANDOR BOX, for nonactivating non-down-regulating) abolishes TGF-beta-dependent mitogenesis, transcriptional activity, type I receptor phosphorylation, and down-regulation in mesenchymal cultures, adjacent mutations also within the kinase domain are without effect. Moreover, a kinase-defective type I receptor can functionally complement a mutant BOX expressing type I receptor, documenting that when the BOX mutant is activated, it has kinase activity. These results indicate that the sequence between 482 and 491 in the type I receptor provides a critical function regulating activation of the TGF-beta receptor complex.