Type III TGF-beta receptor-independent signalling of TGF-beta2 via TbetaRII-B, an alternatively spliced TGF-beta type II receptor

Abstract

Transforming growth factor-b (TGF-b) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-b are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no signi®cant functional redundancy between TGF-b1, -2 and -3. While signal transduction by TGF-b1 has been well characterized, receptor binding and activation by the TGF-b2 isoform is less well understood. Here, we show that TbRII-B, an alternatively spliced variant of the TGF-b type II receptor, is a TGF-b2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-b type III receptor (TbRIII). L6 cells lacking endogenous TbRIII as well as TbRII-B do not respond to TGF-b2. Transfection of these cells with TbRII-B restores TGF-b2 sensitivity. The expression of TbRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-b2 has a predominant role. This re¯ects the importance of this receptor in TGF-b isoform-speci®c signalling.

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

“…4A). The dose-response curve obtained with increasing amounts of TGF-␤2 suggested that the cells are able to signal through TGF-␤2 in the absence of T␤RIII and T␤RII-B, but require higher doses of TGF-␤2 compared with TGF-␤1 or -␤3 (data not shown), as has been previously shown (16).…”

“…It has been suggested that iodinated TGF-␤2 could be cross-linked to T␤RII-B but not T␤RII, thus indicating that the 26-amino acid insert might confer the ability to bind and signal via TGF-␤2 to the type II-B receptor (16). Indeed, the 26-amino acid insert is at the N 1 and 2) or presence of 5 g/ml each of sT␤RII-B.Fc, sT␤RII.Fc, or sT␤RI.Fc alone (lanes 3-5), or of the mixture composed of 5 g/ml each of sT␤RII-B.Fc or sT␤RII.Fc plus sT␤RI.Fc (lanes 6 and 7) as indicated.…”

“…L6 cells lack T␤RIII (11,28) and T␤RII-B (16), but express T␤RII and T␤RI and are thus able to transduce TGF-␤1 signals (16,28). L6 cells were transfected with the (CAGA) 12 MPL-Luc reporter construct and treated with increasing amounts (0 -200 pM) of TGF-␤2 (Fig.…”

“…Cross-linking studies of cell-surface TGF-␤ receptors with 125 I-TGF-␤2 in transfected COS cells have suggested that high affinity TGF-␤2 binding and downstream signaling in these cells can occur via complexes of type I and type II receptors (30). Alternatively, Rotzer et al (16) has proposed that T␤RII-B binds TGF-␤2 with ensuing signaling in the absence of T␤RIII. Of note, an earlier report showing the inability of unlabeled TGF-␤2 to compete for 125 I-TGF-␤1 binding to T␤RII-B inferred that T␤RII-B resembles T␤RII in its inability to bind TGF-␤2 (14).…”

Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome

“…55 Interestingly, the expression of TbR-IIB is restricted to cells originating from mesenchymal tissues such as bone where the isoform TGF-b2 has a predominant role. It would be interesting to investigate an antisense OGN designed against this spliced variant, as it may be more specific in inhibiting TGF-b2-mediated activity.…”