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A Pivotal Role for the Transmembrane Domain in Transforming Growth Factor-β Receptor Activation*

Transforming growth factor-β (TGF-β) delivers diverse growth and differentiation signals by binding two distantly related transmembrane serine/threonine kinase receptors: the type I receptor (TβRI) and the type II receptor (TβRII). In an attempt to establish the role of the transmembrane domain in receptor signaling, two chimeric TGF-β receptors, TβRI-II-I and TβRII-I-II, containing the opposite transmembrane domain were generated. When transfected into a mutant mink lung epithelial cell line R1B, which lacks functional TβRI, TβRI-II-I restored TGF-β1-induced transcriptional activation of a TGF-β reporter p3TP-Lux to ∼25% of the levels restored by wild-type TβRI. In the mutant mink lung epithelial cell line DR26, which contains a truncated, nonfunctional TβRII, wild-type receptor TβRII restored the TGF-β responsiveness, while the TβRII-I-II cDNA was inactive. When both TβRI and TβRII were transfected into R1B, DR26, or Mv1Lu cells, a low level of constitutive p3TP-Lux activity was observed. However, cotransfection of both transmembrane chimeric receptors, TβRI-II-I and TβRII-I-II, or the wild-type TβRI with the transmembrane chimeric TβRII-I-II resulted in high levels of ligand-independent receptor activation. These results suggest that the transmembrane domains of both TGF-β receptors are essential and play a pivotal role in receptor activation. To investigate the role of the transmembrane domain further, four type II transmembrane mutants were generated: TβRIIΔ-1, TβRIIΔ-2, TβRIIΔ-3, and TβRIIΔ-4, which have one, two, three, or four amino acids deleted at the N terminus of the transmembrane domain, respectively. Interestingly, co-expression of TβRIIΔ-1 with the wild-type TβRI in DR26 cells resulted in high levels of constitutive activation, while only low levels of the activation were observed when TβRIIΔ-2, TβRIIΔ-3, or TβRIIΔ-4 were co-expressed with the wild-type TβRI. However, TβRIIΔ-1 restored very little the TGF-β responsiveness in DR26cells. Expression of TβRIIΔ-2, TβRIIΔ-3, and TβRIIΔ-4 resulted in a progressive increase in TGF-β responsiveness, with TβRIIΔ-4 reaching the level of activity of the wild-type TβRII. Furthermore, like TβRII-I-II, co-expression of TβRIIΔ-1 with TβRI-II-I also resulted in high levels of constitutive activation. These results are consistent with an important role for the transmembrane region of the receptors. We further propose a model of receptor activation in which receptor activation occurs via relative orientational rotation.