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Contextual determinants of TGFβ action in development, immunity and cancer

A Publisher Correction to this article was published on 08 May 2018

This article has been updated

Abstract

Few cell signals match the impact of the transforming growth factor-β (TGFβ) family in metazoan biology. TGFβ cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions and various congenital diseases. The effects of the TGFβ family are mediated by a combinatorial set of ligands and receptors and by a common set of receptor-activated mothers against decapentaplegic homologue (SMAD) transcription factors, yet the effects can differ dramatically depending on the cell type and the conditions. Recent progress has illuminated a model of TGFβ action in which SMADs bind genome-wide in partnership with lineage-determining transcription factors and additionally integrate inputs from other pathways and the chromatin to trigger specific cellular responses. These new insights clarify the operating logic of the TGFβ pathway in physiology and disease.

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Fig. 1: The TGFβ–SMAD pathway in the basal and activated states.
Fig. 2: LDTFs and SDTFs as contextual determinants of TGFβ–SMAD action.
Fig. 3: SMAD cooperation with different DNA binding partners.
Fig. 4: Transcriptional determinants of TGFβ regulation of immune cell fate.
Fig. 5: Determinants of TGFβ tumour suppression and its subversion in cancer.

Change history

  • 08 May 2018

    In the section 'Combinatorial ligand perception' of the original article, DMP1 was incorrectly used in place of BMP. This has now been corrected in the HTML and PDF versions of the article.

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Both authors contributed equally to all aspects of the article preparation, including researching data for the article, discussion of content, and writing and editing of the manuscript before submission.

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Correspondence to Joan Massagué.

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Glossary

Signal-driven transcription factors

(SDTFs). Transcription factors that are often ubiquitously expressed but are only switched on in response to activation of a given signalling pathway.

Lineage-determining transcription factors

(LDTFs). Tissue-restricted or cell type-restricted transcription factors that play a dominant role in establishing cellular gene expression patterns, thereby helping to specify cellular identity and function.

Anti-Muellerian hormone

A developmentally restricted TGFβ superfamily member expressed at high levels in male Sertoli cells to guide testicular development and to a lesser extent in female granulosa cells where it regulates follicle development.

Chromatin readers

Proteins containing one or more domains that interact specifically with modified histones, providing a readout of and often enforcing the transcriptional status (active versus silent) of nearby genes.

RAS

A family of small GTPases involved in signal transduction that are activated in response to a number of extracellular signals, often functioning as oncogenes upon constitutive activation by point mutations.

Neddylation

A process analogous to ubiquitylation in which the ubiquitin-like protein NEDD8 is conjugated to target proteins.

Immunoglobulin class switching

Immunoglobulin class switching, also known as class-switch recombination, is a process that switches theproduction of one immunoglobulin isotype to another (e.g. IgM to IgG) in B cells.

PHD domain

A 50–80 amino acid, Cys4-His-Cys3-containing domain found in some chromatin readers, usually displaying a binding preference for lysine-methylated histone tails.

Bromodomain

An approximately 100-amino-acid domain frequently found in chromatin readers, displaying a preference for acetylated lysine residues.

PTEN

A tumour suppressor that restrains activity of the PI3K–AKT pathway through dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate.

Cancer-associated fibroblasts

(CAFs). Fibroblasts present in the tumour stroma that have an important role in promoting tumour growth, invasion and metastasis.

Tumour mutational burden

(TMB). The total number of mutations per coding area of a tumour genome, which is a quantitative index that is used as a biomarker for cancer immunotherapy.

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David, C.J., Massagué, J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol 19, 419–435 (2018). https://doi.org/10.1038/s41580-018-0007-0

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