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Fig. 2. (A) The canonical Smad pathway. TGF-ß bound to the two receptor serine/threonine kinases (type II, light green; type I, blue) initiates signalling by trans-phosphorylation of the type I receptor juxtamembrane domain (red arrow). Signalling ensues with R-Smad phosphorylation (Smad with black dot), oligomerization of R-Smad with Smad4, nuclear translocation and formation of complexes between transcription factors (TF) and co-activators/co-repressors (co) on chromatin. This leads to positive or negative regulation of mRNA synthesis (grey arrow). (B) The inhibitory I-Smad, together with the E3 ligase Smurf, exit the nucleus in response to the incoming TGF-ß signal and bind the receptor complex, leading to shut-down of R-Smad phosphorylation and receptor downregulation.





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