TGF-beta regulates growth and proliferation of cells, blocking growth of many cell types. The TGF-beta receptor includes type 1 and type 2 subunits that are serine-threonine kinases and that signal through the SMAD family of transcriptional regulators. Defects in TGF-beta signaling, includes mutation in SMADs, have been associated with cancer in humans. Prior to activation, receptor regulated SMADs are anchored to the cell membrane by factors like SARA (SMAD Anchor for Receptor Activation) that brings the SMADs into proximity of the TGF receptor kinases. Binding of TGF induces phosphorylation and activation of the TGF-beta R1 receptor by the TGF-beta R2 receptor. The activated TGF-beta R1 phosphorylates SMAD2 and SMAD3, which bind to the SMAD4 mediator to move into the nucleus and form complexes that regulate transcription. SMADs regulate transcription in several ways, including binding to DNA, interacting with other transcription factors, and interacting with transcription corepressors and coactivators like p300 and CBP. SMAD-7 represses signaling by other SMADs to down-regulate the system. Other signaling pathways like the MAP kinase-ERK cascade are activated by TGF-beta signaling, modulate SMAD activation. SnoN also regulates TGF-beta signaling, by binding to SMADs to block transcriptional activation. TGF-beta signaling causes degradation of SnoN, releasing SMADs to regulate transcription, and also activates expression of SnoN, to down-regulate SMAD signaling at later times.
