Heteromeric and Homomeric Transforming Growth Factor-β Receptors Show Distinct Signaling and Endocytic Responses in Epithelial Cells

Abstract Transforming growth factor-β (TGF-β) 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-βR interactions in Mv1Lu epithelial cells. In agreement with that observed in mesenchymal cells, all TGF-βR signaling in Mv1Lu cells required the formation of a heteromeric type I-type II receptor complex. However, the initial endocytic response to TGF-βR oligomerization was distinctly regulated in the two cell types. While heteromeric TGF-β receptors were internalized and down-regulated, homomeric TGF-βR interactions showed diminished endocytic activity in Mv1Lu cells. This contrasts to that observed in mesenchymal cultures where ligand bound to TGF-βR 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-βR 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.