title: Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region.
abstract: The transforming growth factor beta (TGF-beta) type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that contains two inserts in the kinase region and a serine/threonine-rich C-terminal extension. T beta R-II is required for TGF-beta binding to the type I receptor, with which it forms a heteromeric receptor complex, and its kinase activity is required for signaling by this complex. We investigated the role of various cytoplasmic regions in T beta R-II by altering or deleting these regions and determining the signaling activity of the resulting products in cell lines made resistant to TGF-beta by inactivation of the endogenous T beta R-II. TGF-beta binding to receptor I and responsiveness to TGF-beta in these cells can be restored by transfection of wild-type T beta R-II. Using this system, we show that the kinase insert 1 and the C-terminal tail of T beta R-II, in contrast to the corresponding regions in most tyrosine kinase receptors, are not essential to specify ligand-induced responses. Insert 2 is necessary to support the catalytic activity of the receptor kinase, and its deletion yields a receptor that is unable to mediate any of the responses tested. However, substitution of this insert with insert 2 from the activin receptor, ActR-IIB, does not diminish the ability of T beta R-II to elicit these responses. A truncated T beta R-II lacking the cytoplasmic domain still binds TGF-beta, supports ligand binding to receptor I, and forms a complex with this receptor. However, TGF-beta binding to receptor I facilitated by this truncated T beta R-II fails to inhibit cell proliferation, activate extracellular matrix protein production, or activate transcription from a promoter containing TGF-beta-responsive elements. We conclude that the transcriptional and antiproliferative responses to TGF-beta require both components of a heteromeric receptor complex that differs from tyrosine kinase receptors in its mode of signaling.
authors.affiliation: Cell Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
authors.forename: R
authors.initials: R
authors.lastname: Wieser
authors.forename: L
authors.initials: L
authors.lastname: Attisano
authors.forename: J L
authors.initials: JL
authors.lastname: Wrana
authors.forename: J
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000235:genetics; D006801:Humans; D008907:Mink; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004247:DNA; D017346:Protein Serine-Threonine Kinases