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Smad regulation in TGF-ß signal transduction

Ludwig Institute for Cancer Research, Box 595, SE-751 24 Uppsala, Sweden

View larger version (27K): [in a new window]   Fig. 1. Signalling specificity in the TGF-ß superfamily. Classification of the mammalian Smad signalling cascade into activin–TGF-ß (maroon) and BMP (blue) pathways. Representative examples of mammalian ligands (pink shading), type II receptors (red shading), type I receptors (orange shading), R-Smads (green shading), Co-Smads (bright green shading) and I-Smads (grey shading) are depicted in pathways linked by arrows or signs of inhibition. Bifurcation of the TGF-ß pathway at the level of type I receptors towards both TGF-ß and BMP Smads is marked by an asterisk. Nomenclature of proteins not detailed in the text are growth and differentiation factors (GDFs), Mullerian inhibiting substance (MIS), activin type II and type IIB receptor (ActRII/IIB), TGF-ß type II receptor (TßRII), BMP type II receptor (BMPRII), MIS type II receptor (MISRII), activin receptor-like kinases 1 to 6 (ALK1-ALK6). For references see ten Dijke et al. (ten Dijke et al., 2000).

View larger version (17K): [in a new window]   Fig. 2. The Smad family. Diagrammatic representation of the three subfamilies of Smads. The protein diagrams are arbitrarily aligned relative to their C-termini. The MH1 domain is coloured in blue and the MH2 domain in green. Selected domains and sequence motifs are indicated as follows: -helix H2, L3 and H3/4 loops, ß-hairpin, the unique exon 3 of Smad2 (ex3), NLS and NES motifs or putative (?) such motifs, the proline-tyrosine (PY) motif of the linker that is recognised by the Hect domain of Smurfs, the unique SAD domain of Smad4 and the SSXS motif of R-Smads with asterisks indicating the phosphorylated serine residues.

View larger version (24K): [in a new window]   Fig. 3. Smad oligomerisation. Pictorial representation of the plasma membrane receptor kinases that phosphorylate the C-termini of R-Smads (light colour), leading to homo-oligomerisation (a dimer shown for simplicity). Hetero-oligomerisation of R-Smads with the Co-Smad (dark colour) is shown leading to dimers and trimers (see text). The MH1 and MH2 domains are drawn and coloured according to the depiction of Table 1. Small black circles represent the di-phosphate modification of the SXS motif and small, double-headed arrows point to the protein interface between phosphorylated C-termini and the MH2 domain. For references see Chacko et al. (Chacko et al., 2001) and Shi (Shi, 2001).

View larger version (21K): [in a new window]   Fig. 4. Smad signalling centres. Pictorial representation of early signalling events of the Smad pathway. A possible but not yet fully documented signalling scenario is shown, initiating at the plasma membrane. R-Smads (S) anchored to microtubules or filamin become mobilised towards SARA and the receptors where multiprotein centres are organised with the aid of scaffolding proteins containing PDZ domains such as ARIPs (PDZ), additional but yet unknown adaptors (Ad) and R-Smad and Smad4 (S4) anchors-activators such as axin and TRAP-1, respectively. This results in R-Smad phosphorylation and R-Smad–Co-Smad oligomerisation. It is worth noting that a similar signalling scenario might become organised at early endosomes, immediately after receptor-mediated endocytosis. For references see Dong et al. and others (Dong et al., 2000; Furuhashi et al., 2001; Sasaki et al., 2001; Tsuchida et al., 2001; Tsukazaki et al., 1998; Wurthner et al., 2001).

View larger version (24K): [in a new window]   Fig. 5. Smad nucleocytoplasmic shuttling. The five pathways shown are: Smad2 nuclear import after release from SARA (pathway 1); Smad3 nuclear import mediated by importin-ß1 and Ran (pathway 2); Smad4 shuttling mediated by the exportin Crm1 (pathway 3); putative Smad2 (4) and Smad3 (5) export pathways marked with question marks. Horizontal double arrowheaded lines indicate possibilities of Smad oligomerisation in the cytoplasm or nucleus. Smad2 (S2), Smad3 (S3) and Smad4 (S4) are shown as monomers and the actual stoichiometry of the Smad complexes is not depicted here. Small black circles represent the di-phosphate modification of the SXS motif. For references, see Kurisaki et al. (Kurisaki et al., 2001) and Massagué (Massagué, 2000).

View larger version (33K): [in a new window]   Fig. 6. Transcriptional regulation by Smads. Two examples, one for gene induction and one for gene repression are shown. Chromatin in nucleosomal configuration is depicted by an arrow indicating promoter activation and a vertical line depicting promoter silencing. Smads are shown as heterodimers of phosphorylated (small black circle) R-Smad–Smad4 according to Fig. 2. Smads interact with DNA-binding transcription factors (TF) and recruit co-activators (p300) or co-repressors that sequentially associate with HDACs. The former results in transcription factor and histone acetylation (Ac), whereas the latter leads to deacetylation. These models take into account only the role of protein acetylation in transcriptional regulation. For references, see Massagué and Wotton (Massagué and Wotton, 2000).

View larger version (22K): [in a new window]   Fig. 7. Smads in ubiquitin pathways. Six documented examples of Smad-ubiquitin pathways are depicted: (1) Cytoplasmic R-Smad (e.g. Smad1) ubiquitination and proteasomal degradation mediated by Smurfs (Zhu et al., 1999). (2) Cytoplasmic activated R-Smads (e.g. Smad3) target HEF1 for degradation via unknown E3 (?) ligases (Liu et al., 2000). (3) Nuclear R-Smads (e.g. Smad3) target the co-repressor SnoN for degradation via Smurfs or the APC that act as E3 ligases (Bonni et al., 2001; Stroschein et al., 2001). (4) Nuclear R-Smads (e.g. Smad2) are degraded after Smurf-mediated ubiquitination (Lin et al., 2000; Lo and Massagué, 1999; Zhang et al., 2001). (5) Nuclear R-Smads (e.g. Smad3) are ubiquitinated by the action of the SCFFbw1a/Roc1 E3 ligase complex, exported to the cytoplasm and finally degraded there (Fukuchi et al., 2001). (6) The TGF-ß signal induces Smad7-Smurf association, export to the cytoplasm and targeting of the receptor kinases that become degraded (Ebisawa et al., 2001; Kavsak et al., 2000). R-Smads (S, with small black circles indicating C-terminal phosphorylation) and Smad7 (S7) are depicted as circles. The poly-ubiquitin chain is shown as a multi-circle attachment and an X indicates proteasomal degradation of the target protein.

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