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WIREs Dev Biol
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The TGFbeta Superfamily Signaling Pathway

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Abstract The transforming growth factor (TGF)beta superfamily of secreted factors is comprised of over 30 members including Activins, Nodals, Bone Morphogenetic Proteins (BMPs), and Growth and Differentiation Factors (GDFs). Members of the family, which are found in both vertebrates and invertebrates, are ubiquitously expressed in diverse tissues and function during the earliest stages of development and throughout the lifetime of animals. Indeed, key roles in embryonic stem cell self‐renewal, gastrulation, differentiation, organ morphogenesis, and adult tissue homeostasis have been delineated. Consistent with this ubiquitous activity, aberrant TGFbeta superfamily signaling is associated with a wide range of human pathologies including autoimmune, cardiovascular and fibrotic diseases, as well as cancer. TGFbeta superfamily ligands signal through cell‐surface serine/threonine kinase receptors to the intracellular Smad proteins, which in turn accumulate in the nucleus to regulate gene expression. In addition to this universal cascade, Smad‐independent pathways are also employed in a cell‐specific manner to transduce TGFbeta signals. Ligand access to the signaling receptors is regulated by numerous secreted agonists and antagonists and by membrane‐associated coreceptors that act in a context‐dependent manner. Given the fundamental role of the TGFbeta superfamily in metazoans and the diversity of biological responses, it is not surprising that the signaling pathway is subject to tight and complex regulation at levels both outside and inside the cell. WIREs Dev Biol 2013, 2:47–63. doi: 10.1002/wdev.86 This article is categorized under: Signaling Pathways > Cell Fate Signaling

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Smad family architecture. Depicted are the human SMADs 1 to 9 (SMAD9 is mostly referred to as SMAD8). All SMAD proteins share Mad Homology domains MH1 (purple) and MH2 (blue) that mediate interactions with numerous cytoplasmic or nuclear proteins. In addition, the MH1 domain of the R‐SMADs and SMAD4 contains a β‐hairpin (βH) important for DNA interaction. The MH1 domain of the inhibitory SMADs SMAD6 and SMAD7 lacks these conserved residues, and the most abundant isoform of SMAD2 harbors an additional insert (Ex3) that interferes with binding to DNA. All R‐SMADs have a C‐terminal SSXS motif, within which the last two serines are directly phosphorylated by the type I receptor. The L3 loop within the MH2 domain is a key determinant of the specificity of R‐SMAD interaction with TGFB‐like versus BMP‐like type I receptors and is important for mediating contacts with the phosphorylated SXS motif in oligomerized SMADs. The linker PPXY motif is important for interactions with WW domain proteins including the WW‐HECT domain class of E3 ubiquitin ligases and the transcriptional modulators, TAZ/YAP. In SMAD4, the linker encompasses the SMAD Activation Domain (SAD), which is essential for transcriptional activation.

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TGFbeta superfamily coreceptors. Multiple membrane‐bound proteins modulate the activity of TGFbeta superfamily ligands, often in a context‐dependent manner and with varying strength and ligand specificity. The pseudoreceptor Bone Morphogenetic Protein and Activin Membrane‐bound Inhibitor (Bambi) is related to the TGFbeta serine/threonine kinase receptors, but lacks the intracellular kinase domain and thus negatively regulates TGFB and BMP signaling. The glycosylphosphatidylinositol (GPI)‐linked coreceptors of the Repulsive Guidance Molecules (RGM) family enhance signaling by promoting the interaction of BMPs with the receptor complex. The type III receptors, including the membrane‐anchored proteoglycan Tgfbr3 (also known as Betaglycan) and the structurally related coreceptor Endoglin, can facilitate or antagonize ligand binding to the signaling receptors. Binding of Nodal and other Nodal‐like ligands to the GPI‐anchored epidermal growth factor‐like Cripto/FRL‐1/Cryptic (EGF‐CFC) family members Tdgf1 or Cfc1 (better known as Cripto and Cryptic) is essential for activation of the signaling receptors.

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Core components of the TGFbeta/Smad pathway. The components of the core TGFbeta pathway, well conserved across diverse species from Caenorhabditis elegans, Drosophila melanogaster to humans, are listed (right). In general, upon binding of the dimeric ligand (green) to the heterotetrameric type II/type I receptor complex, the constitutively active type II receptor kinase (brown) phosphorylates the type I receptor (orange) and thereby recruits a cytoplasmic R‐Smad (red), which is then phosphorylated by the type I receptor. The R‐Smads then dissociate from the receptors to form a heteromeric complex with the Co‐Smad (blue). Smad complexes accumulate in the nucleus, where they interact with specific DNA binding proteins (orange and green) and recruit either corepressors or coactivators (not shown) to regulate the expression of specific target genes. The I‐Smads (purple) act as potent negative feedback inhibitors by blocking the type I receptor. In general, ligands activate either Bone Morphogenetic Protein (BMP)‐like or TGFB‐like Smad pathways through specific subsets of type I receptors, though some exceptions are known. In C. elegans, pathway members are grouped according to their biological role into the Dauer pathway or the Sma/Mab pathway. The function of TAG‐68 is postulated based on its sequence, while the role of TIG‐2 and TIG‐3 has not been investigated. The vertebrate type I receptors ACVRL1, ACVR1, BMPR1A, ACVR1B, TGFBR1, BMPR1B and ACVR1C are also referred to as ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, and ALK7, respectively.

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Smad‐independent TGFbeta signaling. TGFbeta superfamily receptors can signal independent of Smad proteins to control processes such as TGFB‐induced epithelial‐to‐mesenchymal transition (EMT) and Bone Morphogenetic Protein (BMP)‐induced neurite outgrowth. (a) TGFB‐induced EMT. The polarity protein Par6 interacts with the type I receptor TGFBR1 localized to the tight junctions in epithelial cells. Upon phosphorylation by the type II receptor TGFBR2, Par6 recruits the E3 ubiquitin ligase Smurf1. Smurf1 promotes ubiquitination and subsequent proteasomal degradation of the small GTPase RhoA, which in turn facilitates dissolution of tight junctions and enhancement of EMT. (b) BMP‐induced cytoskeletal remodeling. BMP‐regulated dendritogenesis of cortical neurons requires BMP‐induced CDC42 activation and binding of LIM kinase 1 (LIMK1) and JNK to the carboxy‐terminus of the BMP type II receptor BMPR2. Activated LIMK1 and JNK then induce the remodeling of the actin and microtubule cytoskeletal networks. (c) Mitogen‐activated protein kinase pathway (MAPK) activation by the TGFB receptors. Binding of TGFB ligand induces the recruitment and activation of the ubiquitin ligase TNF‐receptor‐associated factor 6 (TRAF6) which then activates MAP3K7 (better known as TGFB‐associated kinase 1, TAK1) to trigger the p38/JNK MAPK pathway and promote EMT. Besides a well‐known function as serine/threonine kinases, TGFB receptors can also act as tyrosine kinases. Phosphorylation of specific tyrosine residues on the type I and II receptors either by autophosphorylation or by Src kinase allows for binding of the adapter protein Shc1 (also known as ShcA), which is then phosphorylated by the type I receptor at serine and tyrosine residues. Shc1 recruitment of the adapter protein Grb2 and the guanine nucleotide exchange factor (GEF) Sos activates the membrane‐associated small GTPase Ras to trigger the Erk MAPK pathway.

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Receptor endocytosis. Activated receptor complexes can be internalized by clathrin‐coated pits into early endosomes or by caveolin‐positive lipid rafts, and this receptor routing determines signaling outcome. Early endosomes are enriched in the anchor proteins Zfyve9 and 16 (better known as Sara and Endofin) and Hgs which recruit R‐Smads (red) to promote signaling. In contrast, internalization via lipid rafts induces receptor turnover via inhibitory Smads (purple) and Smurf E3 ubiquitin ligases and thus inhibit signaling.

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Extracellular regulation of TGFbeta superfamily ligands. (a) Ligand production, secretion, and extracellular activity. TGFbeta superfamily ligands are produced as proproteins that are targeted by intracellular proteases. After cleavage, the mature ligand remains in a complex with the propeptide, termed the Latency‐associated protein (LAP). In the case of TGFB ligands, this Small Latent Complex (SLC) is bound by Latent TGFB‐Binding Proteins (LTBPs) to form the Large Latent Complex (LLC). After secretion, the LTBP can mediate interactions with components of the extracellular matrix or transmembrane Integrin receptors. Diverse extracellular proteases can cleave the LTBP or LAP to release the mature TGFB from the inhibitory complex. Numerous extracellular proteins, including proteoglycans and collagens as well as freely diffusible inhibitors, can interact with TGFbeta superfamily members and control ligand availability. (b) Extracellular inhibitors control formation of a BMP activity gradient in Drosophila. For the establishment of a dorsal–ventral BMP activity gradient in the early Drosophila embryo, the BMP antagonists Short gastrulation (SOG) and Twisted gastrulation (TSG) have a dual role in regulating the activity of the BMP homologs DPP and SCW. SOG is secreted ventrally (left in the figure), where it binds DPP and SCW and blocks BMP signaling. The formation of this inhibitory complex is greatly enhanced by TSG. However, SOG also diffuses away from its source to the dorsal side (right), thereby enriching the highly active DPP–SCW heterodimer at the dorsal midline and creating a BMP activity gradient. In a final step, the dorsally expressed secreted metalloprotease Tolloid (TLD) cleaves and inactivates SOG, which is again facilitated by TSG. This releases the DPP–SCW complex from inhibition and allows signaling.

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