Type III TGF-β receptor-independent signalling of TGF-β2 via TβRII-β, an alternatively spliced TGF-β type II receptor

Transforming growth factor-beta (TGF-beta) 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-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3, While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that T beta RII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (T beta RIII), L6 cells lacking endogenous T beta RIII as well as T beta RII-B do not respond to TGF-beta2, Transfection of these cells with T beta RII-B restores TGF-beta2 sensitivity. The expression of T beta RII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.