TGF-β signaling pathways. TGF-β ligands bind type I and type II receptors at the cell surface. Subsequently, the type I receptor (ALK5) becomes phosphorylated by the type II receptor. This leads to phosphorylation of SMAD2 and SMAD3, which form a complex with SMAD4. Activated complexes accumulate in the nucleus where they cooperate with DNA-binding cofactors to regulate target gene transcription. SMAD2 and SMAD3 also bind to TIF1γ. In embryonic stem cells, SMAD2/3-TIF1γ recognizes specific chromatin marks, promoting access of SMAD2/3-SMAD4 to otherwise repressed targets. TIF1-γ–SMAD2/3 promotes erythroid differentiation whereas SMAD4-SMAD2/SMAD3 complexes inhibit proliferation. In certain cell types, JNK and p38 are phosphorylated by TAK1 and constitute, together with the PI3K-AKT-FOXO axis, ERK, and PAR6, so-called noncanonical signaling responses to TGF-β. The dashed line indicates unclear molecular mechanism.