title: Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathways of transforming growth factor-beta.
abstract: Proteins in the transforming growth factor-beta (TGF-beta) superfamily exert their effects by forming heteromeric complexes of their type I and type II serine/threonine kinase receptors. The type I and type II receptors form distinct subgroups in the serine/threonine kinase receptor family based on the sequences of the kinase domains and the presence of a highly conserved region called the GS domain (or type I box) located just N-terminal to the kinase domain in the type I receptors. Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signaling. Here we investigated the role of cytoplasmic juxtamembrane region located between the transmembrane domain and the GS domain of T beta R-I by mutational analyses using mutant mink lung epithelial cells, which lack endogenous T beta R-I. Upon transfection, wild-type T beta R-I restored the TGF-beta signals for growth inhibition and production of plasminogen activator inhibitor-1 (PAI-1) and fibronectin. A deletion mutant, T beta R-I/JD1(delta 150-181), which lacks the juxtamembrane region preceding the GS domain, bound TGF-beta in concert with T beta R-II and transduced a signal leading to production of PAI-I but not growth inhibition. Recombinant receptors with mutations that change serine 172 to alanine (S172A) or threonine 176 to valine (T176V) were similar to wild-type T beta R-I in their abilities to bind TGF-beta, formed complexes with T beta R-II, and transduced a signal for PAI-1 and fibronectin. Similar to T beta R-I/JD1 (delta 150-181), however, these missence mutant receptors were impaired to mediate a growth inhibitory signal. These observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta.
authors.affiliation: Department of Oral Pathology, Tokyo Medical and Dental University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saitoh
authors.forename: H
authors.initials: H
authors.lastname: Nishitoh
authors.forename: T
authors.initials: T
authors.lastname: Amagasa
authors.forename: K
authors.initials: K
authors.lastname: Miyazono
authors.forename: M
authors.initials: M
authors.lastname: Takagi
authors.forename: H
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D017931:DNA Primers; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008907:Mink; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D013912:Threonine; D012694:Serine