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Smad regulation in TGF-β signal transduction

2001; The Company of Biologists; Volume: 114; Issue: 24 Linguagem: Inglês

10.1242/jcs.114.24.4359

1477-9137

Aristidis Moustakas, Serhiy Souchelnytskyi, Carl‐Henrik Heldin,

Protein Kinase Regulation and GTPase Signaling

Smad proteins transduce signals from transforming growth factor-β (TGF-β) superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. Phosphorylation of receptor-activated Smads (R-Smads) leads to formation of complexes with the common mediator Smad (Co-Smad), which 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-β. 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 signalling.