Transcriptional Control by the SMADs

Abstract

The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

Intrinsic mechanisms of neuronal axon regeneration

“…Because SMADs have a low binding affinity for DNA, binding generally requires the recruitment of additional transcription factors or epigenetic modifiers 122 . Several binding partners have been previously identified for SMAD2 and SMAD3, including pro-regenerative transcription factors and epigenetic modifiers such as JUN, ATF3, cellular tumour antigen p53 (TP53), p300 HAT and the histone acetyltransferase KAT2B 122 . Whether these interactions occur in neurons after injury and affect transcriptional regulation is yet to be determined.…”

ALK1 signaling in development and disease: new paradigms

“…SMAD3-SMAD4 and SMAD1/5/8-SMAD4 complexes bind to distinct cis regulatory elements and therefore influence expression of different sets of genes. However, SMAD DNA binding affinity is weak and specificity and affinity are influenced by interaction with non-SMAD transcription factors, thereby allowing transcriptional output to reflect the integration of multiple signaling pathways and/or, through interaction with lineage-specific transcription factors, cell-type specificity [106]. How different type I receptors that phosphorylate the same SMAD proteins regulate different gene cohorts and therefore different cellular behaviors is not understood.…”

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

“…TGF‐β subfamily cytokines utilize Smad2 and Smad3 as R‐Smads, while BMPs activate Smad1/5/8. Activated R‐Smads form a complex with Smad4, and together they translocate into the nucleus to regulate target gene transcription in collaboration with other transcription factors or co‐factors . In addition, TGF‐β is capable of activating other signaling pathways mediated by PI3K/Akt, MAPKs (EKR1/2, JNKs and p38), PAK2 and Cdc42/RhoA GTPases, among others …”