RECEPTOR DEGRADATION Smad-Mediated Degradation of the TGF-ß Receptor

Abstract:

Although certain cytosolic Smad proteins transduce signals from an activated transforming growth factor-ß (TGF-ß) receptor at the cell surface to the nucleus, other Smads such as Smad7 negatively regulate TGF-ß signaling when they bind to the receptor. Kavsak et al. report that Smad7 may accomplish this by acting as an adaptor protein that recruits a ubiquitin ligase called Smurf2 to the receptor. Smad7 facilitated the export of Smurf2 from the nucleus to the cytosol, and treatment of cells with TGF-ß stimulated localization of Smad7-Smurf2 complexes to TGF-ß receptors at the cell membrane. It is interesting that Smad7 is ubiquitinated, supporting the notion that some cell-surface receptors may be down-regulated when an associated protein becomes ubiquitinated, hence targeting the entire protein complex for proteasome-mediated degradation. Because other Smad proteins bear the motif that is critical for interaction with Smurf2, it could be that Smads in general may function not only to regulate transcription but also to target specific proteins for destruction in response to TGF-ß signaling.

Kavsak, P., Rasmussen, R.K., Causing, C.G., Bonni, S., Zhu, H., Thomsen, G.H., and Wrana, J.L. (2000) Smad7 binds to Smurf2 to form E3 ubiquitin ligase that targets the TGFß receptor for degradation. Mol. Cell 6: 1365-1375. [Online Journal]