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 biologic al 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, X enopus, and Drosophila type I receptors. Although mutation or deletion of t he region (referred to as the NANDOR BOX, for nonactivating non-down-regula ting) abolishes TGF-beta -dependent mitogenesis, transcriptional activity, type I receptor phosphorylation, and down-regulation in mesenchymal culture s, adjacent mutations also within the kinase domain are without effect. Mor eover, a kinase-defective type I receptor can functionally complement a mut ant BOX expressing type I receptor, documenting that when the BOX mutant is activated, it has kinase activity. These results indicate that the sequenc e between 482 and 491 in the type I receptor provides a critical function r egulating activation of the TGF-beta receptor complex.