title: Two divergent signaling pathways for TGF-beta separated by a mutation of its type II receptor gene.
abstract: Transforming growth factor beta (TGF-beta) can inhibit epithelial cell growth and induce extracellular matrix formation through signal transduction via its two receptors and its downstream intracellular Smad proteins. We recently reported a germline mutation, i.e., substitution of methionine for threonine at codon 315 in the kinase subdomain IV, of the TGF-beta type II receptor gene in a kindred of hereditary nonpolyposis colorectal cancer without microsatellite instability and found that the mutant receptor abolished the signal transduction for growth inhibition by TGF-beta. In this study, we performed further functional analysis of this mutant receptor. The results showed that, in contrast to its failure to mediate growth inhibition by TGF-beta, the mutant receptor still retained the ability to induce one of the extracellular matrix proteins, plasminogen activator inhibitor type 1, upon TGF-beta treatment. However, coincident with its failure to mediate growth inhibition by TGF-beta, the mutant receptor failed to transcriptionally upregulate one of the cyclin-dependent kinase inhibitors, p15(INK4B), in response to TGF-beta. These data suggest that threonine 315 of the TGF-beta type II receptor is dispensable for extracellular matrix protein production, but is essential for the growth inhibition by TGF-beta, and that the lack of growth inhibition due to the mutant receptor is possibly mediated through its failure to upregulate p15(INK4B).
authors.affiliation: Department of Hygiene and Oncology, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Tokyo, Bunkyo-ku, 113-8519, Japan.
authors.forename: S L
authors.initials: SL
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Kawabata
authors.forename: T
authors.initials: T
authors.lastname: Imamura
authors.forename: K
authors.initials: K
authors.lastname: Miyazono
authors.forename: Y
authors.initials: Y
authors.lastname: Yuasa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005109:Extracellular Matrix / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D008168:Lung / Q000378:metabolism; D008907:Mink; D008969:Molecular Sequence Data; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases