Anti-Smad5: Mouse Smad5 Antibody

Smad proteins transduce signals from transforming growth factor-beta (TGF-beta) superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. It has been demonstrated that accessory/scaffolding proteins interact with the type I and II receptors and/or the Smads. One example is SARA (Smad anchor for receptor activation), a cytoplasmic protein that specifically interacts with non-activated Smad2 and the receptor complex, thus forming a bridge between the receptor and Smad2 and assisting in the specific phosphorylation of Smad2 by the type I receptor. The mechanism that organises such Smad signaling centres and its links to receptor endocytosis, degradation and signaling crosstalk could provide cell-context specificity, allowing differential regulation of the basic Smad pathway.²

Phosphorylation of the C-terminal serine residues in R-Smads by type I receptor kinases is a crucial step in TGF-beta family signaling. The two most C-terminal serine residues become phosphorylated and, together with a third, non-phosphorylated serine residue, form an evolutionarily conserved SSXS motif in all R-Smads. TGF-beta and activin receptors phosphorylate Smad2 and Smad3, and BMP receptors phosphorylate Smad1, Smad5 and Smad8. Other kinases might also phosphorylate the Smads, which include MAPK, CaMK II and PKC.³ Unphosphorylated Smad proteins exist primarily as monomers, and upon phosphorylation, R-Smads form homo-oligomers, which quickly convert to hetero-oligomers containing the Co-Smad, Smad4 and are imported to the nucleus. Nuclear Smad oligomers bind to DNA and associate with transcription factors to regulate expression of target genes. Alternatively, nuclear R-Smads associate with ubiquitin ligases and promote degradation of transcriptional repressors, thus facilitating target gene regulation by TGF-beta. Smads themselves can also become ubiquitinated and are degraded by proteasomes. Finally, the inhibitory Smads (I-Smads) block phosphorylation of R-Smads by the receptors and promote ubiquitination and degradation of receptor complexes, thus inhibiting signaling.⁴