Signaling activity of homologous and heterologous transforming growth factor-β receptor kinase complexes Journal Article
| Authors: | Vivien, D.; Attisano, L.; Wrana, J. L.; Massagué, J. |
| Article Title: | Signaling activity of homologous and heterologous transforming growth factor-β receptor kinase complexes |
| Abstract: | Transforming growth factor-β (TGF-β) signaling in Mv1Lu lung epithelial cells requires coexpression of TGF-β receptors I (TβR-I) and II (TβR-II), two distantly related transmembrane serine/threonine kinases that form a heteromeric complex upon ligand binding. Here, we examine the formation of TGF-β receptor homooligomers and their possible contribution to signaling. TβR-I can contact ligand bound to TβR-II, but not ligand free in the medium, and thus cannot form ligand-induced homo-oligomers. TβR-II, which binds ligand on its own, formed oligomeric complexes when overexpressed in transfected COS cells. However, these complexes were largely ligand- independent and involved immature receptor protein. Since ligand-induced homooligomers could not be obtained with the wild-type TGF-β receptors, we studied receptor cytoplasmic domain homo-oligomerization by using receptor chimeras. The extracellular domain of TβR-II was fused to the transmembrane and cytoplasmic domains of TβR-I, yielding TβR-II/I, and the extracellular domain of TβR-I was fused to the transmembrane and cytoplasmic domains of TβR-II, yielding TβR-I/II. When cotransfected with wild-type receptors and exposed to ligand, TβR-II/I formed a complex with TβR-I, and TβR-I/II formed a complex with TβR-II, thus yielding complexes with homologous cytoplasmic domains. TβR-II/I transfected alone or with TβR-I did not restore TGF-β responsiveness in TβR-II-defective cell mutants. Furthermore, TβR-II/I acted in a dominant negative fashion, inhibiting restoration of TGF-β responsiveness by a cotransfected TβR-II in TβR-II-defective cells and by a cotransfected TβR-I in TβR-I-defective cells. Similarly, TβR- I/II transfected alone or with TβR-II did not restore TGF-β responsiveness and acted in a dominant negative fashion against TβR-I. Together with previous genetic and biochemical evidence, these results suggest that TGF-β mediates transcriptional and antiproliferative responses through the heteromeric TβR-I·TβR-II complex and not through homo-oligomeric TβR-I or TβR-II complexes. |
| Keywords: | signal transduction; nonhuman; polymerase chain reaction; protein domain; animal cell; animal; transforming growth factor beta; cell line; luciferase; transfection; cercopithecus aethiops; kidney; transcription regulation; kinetics; protein-serine-threonine kinases; cell membrane; receptors, transforming growth factor beta; epithelium cell; receptor protein-tyrosine kinases; ligand binding; receptor binding; electrophoresis, polyacrylamide gel; mink; receptor subtype; lung alveolus epithelium; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; chimeric proteins |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 270 |
| Issue: | 13 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 1995-03-31 |
| Start Page: | 7134 |
| End Page: | 7141 |
| Language: | English |
| DOI: | 10.1074/jbc.270.13.7134 |
| PUBMED: | 7706250 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 28 August 2018 -- Source: Scopus |
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