1. TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders
Joan Massagué, Stacy W Blain, Roger S Lo 
Cell 
Volume 103, Issue 2, Pages (October 2000)
DOI: /S (00)

2. Figure 1 The Basics of TGFβ Signaling
A ligand-induced receptor complex phosphorylates a member of the R-Smad class (Smads1, 2, 3, 5, or 8), enabling its association with Smad4 and accumulation in the nucleus. In the nucleus, the activated Smad complex associates with two classes of proteins: DNA binding cofactors that will help select target genes, and coactivators or corepressors that will determine the transcriptional effect on the target genes. Smads have intrinsic nuclear import activity, but, at least in the case of Smad2/3, these proteins are retained in the cytoplasm by binding to SARA. Receptor-mediated phosphorylation of a R-Smad decreases its affinity for SARA and increases its affinity for Smad4.
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3. Figure 2 Ligand, Receptor, and Smad Relationships in the TGFβ System
Two branches of the Smad pathway mediate signaling by the two main groups of TGFβ family agonists. The TGFβs, Activins, and Nodals (and the Nodal-related Xnr factors from Xenopus) engage receptors that phosphorylate Smads 2 and 3. The BMPs and related GDFs, as well as AMH/MIS, engage receptors that signal through Smads 1, 5, and 8. Orthologs from Drosophila are listed in red color. Alternative type I receptor names are: ALK3 (BMPR-IA), ALK4 (ActR-IB), ALK5 (TβR-I) and ALK6 (BMPR-IB). Activins and BMPs share some of their type II receptors, as indicated. Activated R-Smads share co-Smads but not DNA binding cofactors. Smad4β has been reported only in Xenopus. The DNA binding cofactors belong to structurally different protein families (see text for details). BMP, bone morphogenetic protein; GDF, growth and differentiation factor; DPP, decapentaplegic; and AMH/MIS, anti-Müllerian hormone/Müllerian inhibiting substance.
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4. Figure 3 Smad Functional Domains and Cancer Mutations
The MH1 and MH2 domains are conserved in all R-Smads and co-Smads and form globular structures. They are linked by a more divergent region. The functions of these three regions are listed. Identification of the DNA binding site (hairpin) is based on the crystal structure of the Smad3 MH1 domain bound to its cognate sequence (Shi et al. 1998). The Smad interacting regions in the MH2 domain are based on the crystal structure of this domain in Smad4 (Shi et al. 1997). The multiple contact sites with SARA are based on the crystal structure of a SARA–Smad2 complex (Wu et al, 2000). Other protein interaction sites have been defined by site-directed mutagenesis. Tumor-derived mutations are indicated by black bars for Smad4 and red bars for Smad2.
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5. Figure 4 TGFβ Pathway Integration into a Signaling Network
A signaling network controls the activity of the TGFβ/Smad pathway at multiple levels. Only a few representative examples are shown. Noggin, Caronte, and LAP are inhibitors of ligand binding to the signaling receptors. Betaglycan and endoglin are enhancers of ligand-access to the signaling receptors. FKBP12 keeps the type I receptors in the basal state. BAMBI is a truncated receptor-like protein that inhibits type I receptor activation. Smurf is an E3 ubiquitin ligase that mediates Smad degradation. Smad7 and Smad6 are decoy Smads that interfere with receptor interaction with R-Smads or R-Smad interaction with Smad4. Erk MAP kinase phosphorylation attenuates nuclear accumulation of the Smads. TGIF, Ski, and SnoN are Smad transcriptional corepressors. TGIF competes with the coactivatior p300 for binding to the Smad complex. The level or activity of several of these components is controlled by diverse signals as indicated.
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6. Figure 5 The Cell Cycle Arrest Response to TGFβ
(A) Two classes of antiproliferative gene responses are known to be induced by TGFβ. The first is c-Myc downregulation, observed in most cell types that are growth inhibited by TGFβ. The second are cdk-inhibitory responses, including the induction of p15 and p21 and the downregulation of cdc25A. Most cells that are growth inhibited by TGFβ have different combinations of cdk-inhibitory responses. c-Myc antagonizes TGFβ signaling by acting as a repressor of cdk-inhibitory responses. Downregulation of c-Myc is thus necessary for TGFβ-induced cell cycle arrest. Loss of cdc25A and the induction of p21 or p15 lead to the direct inhibition of cyclin D-cdk4.
(B) p15 binding to cyclin D-cdk4 leads to the shuttling of p27 from active cyclin D-cdk4-p27 complexes to cyclin E-cdk2 complexes, resulting in their ultimate inhibition as well.
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7. Figure 6 Heritable Mutations in the TGFβ Pathway
Mutations that target components of the TGFβ signaling pathway contribute to diverse human disorders. The basic signaling components are indicated with similar icons as those depicted in Figure 1. The modes of inheritance and the mechanisms of disease are discussed in the text.
Cell  , DOI: ( /S (00) )