Transforming growth factor beta receptor signaling and endocytosis are linked through a COOH terminal activation motif in the type I receptor.
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.
Garamszegi
N
N
Thoracic Diseases Research Unit, Mayo Clinic, Rochester, MN 55905, USA.
Doré
J J
JJ
Penheiter
S G
SG
Edens
M
M
Yao
D
D
Leof
E B
EB
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D005347:Fibroblasts; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D051899:Smad2 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D015534:Trans-Activators; D016178:Granulocyte-Macrophage Colony-Stimulating Factor