Heteromeric and homomeric transforming growth factor-beta receptors show distinct signaling and endocytic responses in epithelial cells.
Transforming growth factor-beta (TGF-beta) induces distinct responses dependent upon the cellular context. It is unclear whether the initial receptor interactions identified in one cell type will be operative in another. Utilizing a chimeric receptor strategy we have examined the signaling and endocytic activity of both heteromeric (type I/type II) and homomeric (type I/type I or type II/type II) TGF-betaR interactions in Mv1Lu epithelial cells. In agreement with that observed in mesenchymal cells, all TGF-betaR signaling in Mv1Lu cells required the formation of a heteromeric type I-type II receptor complex. However, the initial endocytic response to TGF-betaR oligomerization was distinctly regulated in the two cell types. While heteromeric TGF-beta receptors were internalized and down-regulated, homomeric TGF-betaR interactions showed diminished endocytic activity in Mv1Lu cells. This contrasts to that observed in mesenchymal cultures where ligand bound to TGF-betaR homomers was internalized, yet the receptors were not down-regulated. Moreover, while previous reports have suggested that mutations at serine 172 or threonine 176 in the type I TGF-betaR separated transcriptional from proliferative responses, we found no separation of pathways or effect on initial endocytic activity when the analogous mutations were made in the chimeric receptors.
Doré
J J
JJ
Thoracic Disease Research Unit and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Edens
M
M
Garamszegi
N
N
Leof
E B
EB
D030201:Activin Receptors, Type I; D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D007700:Kinetics; D008168:Lung; D046911:Macromolecular Substances; D008907:Mink; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction / Q000502:physiology*; D013912:Threonine; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology
D016326:Extracellular Matrix Proteins; D046911:Macromolecular Substances; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D013912:Threonine; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II