Type III TGF-beta receptor-independent signalling of TGF-beta 2 via T betaRII-beta, an alternatively spliced TGF-beta type II receptor

Transforming growth factor-beta (TGF-beta) signals through membrane-bound s erine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcription al activity. Although the three mammalian isoforms of TGF-beta are highly h omologous at the level of sequence, analysis of their in vivo function by g ene knockouts revealed striking differences, suggesting no significant func tional redundancy between TGF-beta1, -2 and -3, While signal transduction b y 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 R II-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathw ay 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 T GF-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 originat ing 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-sp ecific signalling.