Regulators of Smad2/3 Transcription and Phosphorylation

Abstract

Transforming growth factor beta (TOF-B) is a multifunctional cytokine that controls a wide variety of cellular processes, such as cell migration, adhesion, differentiation, proliferation, and cell death. Disruption of components of the TGF-B signaling pathway is associated with human diseases, including cancer. TOF-B initiates signaling from the cell surface by contacting two distantly related transmem- brane serine/threonine kinases called receptors I (TBRI) and II (TBRII). Upon ligand binding, the constitutively active TBRII phosphorylates and activates TBRI, which in turn phosphorylates Smad2 or Smad3 on two serines at the carboxyl terminus, within a highly conserved SSXS motif. Following phosphorylation, Smad2 and Smad3 associate with the shared partner Smad4 and translocate to the nucleus where Smad complexes, in cooperation with coactivators and corepressors, participate in transcriptional regulation of TGF-B-responsive genes. Smad phosphorylation, cellular distribution. and activation are tightly regulated via crosstalk with other signaling pathways or through func- tional interactions with Smad partners and modulators that determine the specific target genes. The present knowledge of the mechanisms controlling phosphorylation and activation of Smad proteins is reviewed here.