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How cells read TGF-β signals

Nature Reviews Molecular Cell Biology volume 1, pages 169–178 (2000)Cite this article

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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Recent data indicates that TGF-βs may also signal through the mitogen-activated protein kinase (MAPK) pathways.

  • 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.

  • 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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Figure 1: The basic SMAD pathway.
Figure 2: A network controlling a pathway.
Figure 3: SMADs interact with DNA-binding cofactors to specify TGF-β gene responses.
Figure 4: Crosstalk between the SMAD and mitogen-activated protein kinase pathways.
Figure 5: Self-modifying signals.

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Authors and Affiliations

  1. Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, Box 116, 1,275 York Avenue, New Yorkc, 10021, New York, USA

    Joan Massagué

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  1. Joan Massagué
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DATABASE LINKS

TGF-β

SMADs

type I receptors

type II receptors

GS region

SMURF1

BMPs

GDFs

AMH

SMAD1

SMAD5

SMAD8

Activin

Nodal

SMAD2

SMAD3

SMAD4

p300

CBP

MSG-1

SARA

FYVE domain

importin-α

Xnr-1

Xnr-2

Vg1

BMP4

SMAD7

OAZ

FAST

Mixer

JUNB

TFE3

AML

LEF1

Wnts

β-catenin

Xtwn

TGIF

SKI

SnoN

ERK

HPE

cyclops

JNK

p38

MKK4

MKK3

TAK1

Interleukin-1

Rho family

Jun

Fos

ATF2

fibronectin

TNF-α

HH

DPP

thickveins

IFN-γ

JAK

STAT

NK-κB

Ras

EGF

MAD

wingless

twist

tinman

pointed

Drosophila EGF receptor

eve

BAMBI

SMAD6

LAP

Follistatin

Noggin

Chordin

Caronte

Cerberus

Gremlin

Betaglycan

Endoglin

Inhibin

Thrombospondin

CBFA1

CBFA2

CBFA3

IgCα

cleidocranial dyplasia

BMP7

Goosecoid

FURTHER INFORMATION

Massagué lab homepage

ENCYCLOPEDIA OF LIFE SCIENCES

Bone morphogenetic proteins and their receptors

Vertebrate embryo: Establishment of left?right asymmetry

Xenopus embryo: Neural induction

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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