Figure 2. The proteomic organization of three subfamilies of Smads (Co-Smad, R-Smad and I-Smad) and organization of a Smad MH1 domain with DNA. (A) All Smads information taken from PDB entry Smad>UniProt Gene list of Smads. The conserved N-terminal MH1 domain is in red, linker region in dark blue and the C-terminal MH2 domain in deep yellow. In the linker region the red PXS/TP (or S/TP) indicates the potential phosphorylation site for MAPKs ERK1/2, and the square indicates the PY (proline-tyrosine) motif that is recognized by the Hect/ WW domain of Smurfs. The other domains and motifs are marked as follows: α-helix H1, H2, L3 and H3/4 loops, β–hairpin (β-h) that binds to DNA, the unique exon 3 of Smad2 (ex3), NLS (nuclear localization signal)
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Smad proteins in the resting state realize passive nucleo cytoplasmic shuttling, that is controlled by two opposing signals: the nuclear localization signal (NLS) in the MH1 domain and the nuclear export signal (NES) in the MH2 domain. Then they interact with DNA binding proteins or directly regulate transcriptional activity, either as monomers or in association with Smad4 (Carreira et al., 2014 [6]; Liu et al., 1996 [49]). In the nucleus they can regulate transcription of target genes by directly binding via their MH1 domain to specific DNA sequences depends on the formation of Smad complex with other DNA-binding proteins. The R-Smad/C-Smad heterodimer complex interacts with various transcription factors, co-activators and co-repressors to modulate gene expression (ten Dijke et al., 2000 [46]; Kusanagi et al., 2000 [50]). Smad complex binds the promotor regions of several BMP-responsive genes. Recently, the BMP-responsive region in the Id1 promoter has been identified with two critical motifs, i.e. SBEs (Smad-binding element) and GC-rich boxes (TGGCGCC) (Mukhopadhyay et al., 2008 [51], Morikawa et al., 2011 [52]). The sequence TGGCGCC (Bre7 motif) is located a short distance upstream of one or more SBEs motifs containing GTCTG. In the nucleus, Smads are also able to participate in histone modifications and chromatin remodeling (Ross et al., 2006 [53]). Anyway, some transcription factors like Runx1, Runx2, and Runx3 in concert with R-Smads and/or Smad complex plays critical roles in mediating specific signals to regulate the transcription of ultimate target genes. Essentially, Runx2 regulate osteoblasts formation and activate the expression of other osteogenesis specific target genes. The β subunit of PEBP2 stabilizes Runx2 by preventing ubiquitin-dependent degradation (James, 2013 [54]). Upon activation of BMP
Smad proteins in the resting state realize passive nucleo cytoplasmic shuttling, that is controlled by two opposing signals: the nuclear localization signal (NLS) in the MH1 domain and the nuclear export signal (NES) in the MH2 domain. Then they interact with DNA binding proteins or directly regulate transcriptional activity, either as monomers or in association with Smad4 (Carreira et al., 2014 [6]; Liu et al., 1996 [49]). In the nucleus they can regulate transcription of target genes by directly binding via their MH1 domain to specific DNA sequences depends on the formation of Smad complex with other DNA-binding proteins. The R-Smad/C-Smad heterodimer complex interacts with various transcription factors, co-activators and co-repressors to modulate gene expression (ten Dijke et al., 2000 [46]; Kusanagi et al., 2000 [50]). Smad complex binds the promotor regions of several BMP-responsive genes. Recently, the BMP-responsive region in the Id1 promoter has been identified with two critical motifs, i.e. SBEs (Smad-binding element) and GC-rich boxes (TGGCGCC) (Mukhopadhyay et al., 2008 [51], Morikawa et al., 2011 [52]). The sequence TGGCGCC (Bre7 motif) is located a short distance upstream of one or more SBEs motifs containing GTCTG. In the nucleus, Smads are also able to participate in histone modifications and chromatin remodeling (Ross et al., 2006 [53]). Anyway, some transcription factors like Runx1, Runx2, and Runx3 in concert with R-Smads and/or Smad complex plays critical roles in mediating specific signals to regulate the transcription of ultimate target genes. Essentially, Runx2 regulate osteoblasts formation and activate the expression of other osteogenesis specific target genes. The β subunit of PEBP2 stabilizes Runx2 by preventing ubiquitin-dependent degradation (James, 2013 [54]). Upon activation of BMP