Signaling pathways triggered by TGF-β. Active TGF-β binds to a dimer of TGF-βRII, which associates with a dimer of TGF-βRI to form a tetrameric receptor complex. TGF-βRII then phosphorylates the cytoplasmic domain of TGF-βRI, which activates the kinase activity of TGF-βRI. TGF-βRI can then associate with and phosphorylate receptor Smads (Smad2 or 3), which subsequently form a complex with either Smad4 or TIF1γ. The activated Smad complexes then act to modulate gene expression by binding to Smad-responsive elements in genes. TGF-β receptor activation can also trigger non-Smad-mediated signaling events (e.g., via MAPK, Rho GTPases, or PI3 kinase) to regulate gene expression.