The TGF-β signaling pathway and mechanisms of inhibition during leukemogenesis. TGF-β binds TβRII, directly or through TβRIII, inducing association of TβRII with TβRI. TβRII then phosphorylates and activates TβRI, which then phosphorylates Smad2 or Smad3. SARA acts to concentrate Smad2/3 near the cell surface, facilitating their phosphorylation by TβRI. Phosphorylated Smad2/3 associate with Smad4 and translocate into the nucleus, where they activate transcription of target genes. Smad7 inhibits TGF-β signaling by preventing TβRI's activation of Smad2/3. In leukemias, disease-specific oncoproteins disrupt this pathway through different mechanisms. PML-RARα prevents the phosphorylation of Smad2/3 by interrupting the formation of TGF-β receptor/SARA/Smad complexes. AML/ETO, AML/EVI-1, and Evi-1 inhibit Smad3 DNA binding and recruit the transcription repressor, CtBP. Tax disrupts the interaction of Smads with the transcriptional coactivator CBP/p300 and blocks the formation of Smad2/3/4 complexes.