A TGF-β dimer is shown binding to a homodimer of TGFβRII, which then recruits a TGFβRI homodimer. The heterotetrameric complex allows TGFβRI to undergo serine-threonine phosphorylation, which activates its kinase activity and phosphorylates Smad2 and Smad3. These phosphorylated Smad proteins associate with Smad4, and the resultant complex translocates to the nucleus, where it can interact with coactivators such as AP1, Sp1, FAST-1 and the related transcription factor FAST-2, p300, TFE3, and OAZ (8–10) and corepressors (not shown) to modulate gene transcription. For example, genes encoding p21, p15, and p27 are upregulated through interactions between Smad2/3/4-coactivator complexes and Smad-binding elements (SBE). The upregulated proteins then act to inhibit cell-cycle progression and proliferation.