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Vol. 12, Issue 9, 2881-2893, September 2001
Receptor Signaling and Endocytosis
Are Linked through a COOH Terminal Activation Motif in the Type I
Receptor
Thoracic Diseases Research Unit and Department of
Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
55905
Transforming growth factor 
(TGF-) 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- 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--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- receptor complex.
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