Fig. 1.

TGF-β transduces signaling through Smad and non-Smad signaling pathways. Smad pathway (right): TGF-β binds to TβRII and TβRI. TβRII phosphorylates TβRI, which activates Smad2 and Smad3. Activated Smad2/3 form complexes with Smad4, and translocate into the nucleus. The Smad complexes interact with various transcription factors and transcriptional co-activators, and regulate the transcription of target genes. Non-Smad pathways (left): TGF-β signals through multiple intra-cellular signaling cascades other than the Smad pathway. TGF-β receptors activate Erk, JNK, and p38 MAP kinases, PI3 kinase, and small GTPases such as Cdc42 and Rac. TGF-β receptors also bind Par6, induce TβRII kinase to phosphorylate Par6, and recruit Smurf1. Smurf1 then induces ubiquitylation and degradation of substrates such as RhoA.