Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation.

ABSTRACT

The transforming growth factor-beta (TGFbeta) superfamily controls a plethora of biological responses, and alterations in its signalling pathway are associated with a range of human diseases, including cancer. TGFbeta superfamily ligands signal through a heteromeric complex of Ser/Thr kinase receptors that propagate the signal to the Smad family of intracellular proteins. The ubiquitin-mediated proteasomal degradation pathway is an evolutionary conserved cascade that tightly regulates TGFbeta superfamily signalling. Both the size of the Smad pool in unstimulated cells and Smad protein levels subsequent to the activation of the pathway are controlled by ubiquitination. E3 ligases are components of the ubiquitin-degradation complex that specifically recognize targeted proteins and the E3 ligases, Smad ubiquitination-related factor 1 (Smurf1), Smurf2 and SCF/Roc1 have been implicated in Smad degradation. The Smurfs are of particular importance to TGFbeta signalling, as Smads also function as adapters that recruit the Smurfs to various pathway components including the TGFbeta receptor complex and the transcriptional repressor, SnoN, and thereby regulate the degradation of these Smad-associating proteins. Thus, by controlling the level of Smads as well as positive and negative regulators of the pathway, Smurfs provide for complex and fine control of signalling output. Finally, growing evidence demonstrates that ubiquitination and proteasomal degradation is also implicated in the turnover of tumor-derived Smad mutants and may thus contribute to disease progression.