Abstract
Cell proliferation, differentiation and death are controlled by a multitude of cell?cell signals, and loss of this control has devastating consequences. Prominent among these regulatory signals is the transforming growth factor-β (TGF-β) family of cytokines, which can trigger a bewildering diversity of responses, depending on the genetic makeup and environment of the target cell. What are the networks of cell-specific molecules that mould the TGF-β response to each cell's needs?
Key Points
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A cell can respond to a transforming growth factor-β (TGF-β) signal in a multitude of ways. This review emphasizes both the complex network of cross-talking signals that constitute it, and the importance of cellular context in determining the outcome of a signal.
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In organisms ranging from worms to humans, the TGF-β signal is transduced to the nucleus through the action of SMADs. Different TGF-β members act through specific SMADs. The specificity of recptor?SMAD interactions is dictated by discrete structural elements in the receptor kinase domain and the MAD homology domain of the SMAD.
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The numerous members of the TGF-β family initiate signalling by assembling a membrane receptor complex. In this complex, two type II receptor subunits phosphorylate and activate two type I receptor subunits that then propagate the signal by phosphorylating SMAD proteins.
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In the basal state, SMADs are retained in the cytoplasm so that they are accessible to activated receptors. Upon phosphorylation, SMADs move to the nucleus where they control transcription.
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The SMADs can potentially activate many different genes, but their affinity for DNA is too low to do that alone. Cofactors are involved that simultaneously contact a SMAD and a specific DNA sequence. The combined DNA-binding specificity of a SMAD-cofactor complex dictates the choice of target gene.
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Whereas some SMAD cofactors function solely as DNA-binding adaptors, others have intrinsic transcription factor activity. The latter, because they are themselves regulated by extracellular signals, provide a basis for integration of different inputs at the transcriptional level.
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SMADs recruit not only co-activators but also corepressors. They are thought to mediate repression through binding to histone deacetylases, whose effects generally lead to chromatin condensation.
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Recent data indicates that TGF-βs may also signal through the mitogen-activated protein kinase (MAPK) pathways.
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Further control is provided by the regulation of ligand production and negative feedback, which occurs both at the level of the TGF-β receptors and through the action of antagonistic SMADs.
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Inputs that control the level of a SMAD signal can have both quantitative and qualitative effects on the repsonse, because some inputs can activate different sets of genes at different signal thresholds.
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Bone morphogenetic proteins and their receptors
Glossary
- SMADS
-
A family of transcription factors that mediate TGF-β signals. The term SMAD is derived from the founding members of this family, the Drosophila protein MAD (Mothers Against Decapentaplegic) and the Caenorhabditis elegans protein SMA (Small body size).
- GS REGION
-
Regulatory region in TGF-β receptors.
- UBIQUITYLATION
-
The attachment of the protein ubiquitin to lysine residues of other molecules, often as a tag for their rapid cellular degradation.
- PROTEASOME
-
Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.
- UBIQUITIN LIGASE
-
An enzyme that couples the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome.
- NUCLEAR LOCALIZATION SIGNAL
-
A 7?9 residue sequence within a protein, rich in basic residues, which acts as a signal for localization of the protein within the nucleus.
- MESODERM
-
The middle of the three embryonic germ layers, and the source of structures including bone, muscle, connective tissue and dermis.
- MH1 AND MH2 DOMAIN
-
Conserved amino-terminal and carboxy-terminal globular domains, respectively, of SMAD proteins.
- ENHANCER ELEMENT
-
Sequence in the regulatory region of a gene, recognized by factors that enhance the activity of the transcriptional promoter.
- HYPOMORPHIC ALLELE
-
A mutant gene having a similar but weaker function than the wild-type gene.
- IMAGINAL DISC
-
Single-cell layer epithelial structures of the Drosophila larva that give rise to wings, legs and other appendages.
- CHONDROCYTE
-
Differentiated cell of cartilage tissue.
- OSTEOBLAST
-
A mesenchymal cell with capacity to differentiate into bone tissue.
- ECTODERM
-
The outer of the three embryonic germ layers, which gives rise to epidermis and neural tissue.
- ASTROCYTES
-
Star-shaped cells that support the tissue of the central nervous system.
- IMMUNOGLOBULIN-α CONSTANT REGION
-
Region of an antibody molecule that is constant within ? and defines ? each of the basic classes of immunoglobulin.
- ANTIBODY CLASS SWITCHING
-
Process by which the region of an immunoglobulin heavy-chain gene that encodes the antigen recognizing (variable) portion is recombined with the constant region of a different immunoglobulin class.
- MESENCHYME
-
Loosely organized, undifferentiated mesodermal cells.
- MESOENDODERM
-
Gives rise to both the mesoderm and the endodermal tissue of the embryo.
- DORSAL MARGINAL ZONE
-
Region of the Xenopus embryo that gives rise to the dorsal mesoderm.
- GASTRULA
-
Multilayered embryo with an outer cell layer (ectoderm), an inner cell layer (endoderm), and an intermediate cell layer (mesoderm).
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Massagué, J. How cells read TGF-β signals. Nat Rev Mol Cell Biol 1, 169–178 (2000). https://doi.org/10.1038/35043051
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DOI: https://doi.org/10.1038/35043051
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