title: Functional characterization of transforming growth factor beta type II receptor mutants in human cancer.
abstract: We recently identified missense mutations at amino acid residues 526 and 537 located within the highly conserved subdomain XI of the transforming growth factor beta type II receptor (TbetaR-II) serine-threonine kinase in two human squamous carcinoma cell lines. These cell lines are resistant to transforming growth factor beta-mediated inhibition of growth. Moreover, treatment with transforming growth factor beta fails to increase the levels of type 1 plasminogen activator inhibitor and fibronectin synthesis. To test the effects of the mutations on receptor function, mutant TbetaR-II cDNAs were expressed in TbetaR-II-deficient T47D cells. Cyclin A promoter activity was reduced by 50% in cells expressing wild-type TbetaR-II but increased 2-fold in cells transfected with either of the two mutant receptors. Conversely, plasminogen activator inhibitor type 1 promoter activity was increased 6-fold in cells transfected with wild-type receptor but not with either of the two mutant receptors. Moreover, the activity of both mutant serine-threonine kinases was strongly reduced compared to that of the wild-type receptor. Thus, the amino acid residues at positions 526 and 537 seem to be essential for kinase function and signaling activity of the TbetaR-II.
authors.affiliation: Department of Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
authors.forename: M
authors.initials: M
authors.lastname: De
authors.forename: W
authors.initials: W
authors.lastname: Yan
authors.forename: R R
authors.initials: RR
authors.lastname: de Jonge
authors.forename: L
authors.initials: L
authors.lastname: Garrigue-Antar
authors.forename: V F
authors.initials: VF
authors.lastname: Vellucci
authors.forename: M
authors.initials: M
authors.lastname: Reiss
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002455:Cell Division; D003001:Cloning, Molecular; D005353:Fibronectins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II