Review Article | Published:

TGFβ signalling in context

Nature Reviews Molecular Cell Biology volume 13, pages 616630 (2012) | Download Citation

Abstract

The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.

Key points

  • The effects of transforming growth factor-β (TGFβ) are different depending on the cellular context. Three kinds of contextual determinants shape the TGFβ response: the signal transduction components, the transcriptional cofactors of SMAD mediators and the epigenetic state of the cell.

  • TGFβ receptors signal through the canonical SMAD pathway that controls the expression of hundreds of genes, and several non-canonical pathways that regulate cell polarity, the cytoskeleton and microRNA maturation.

  • SMAD proteins regulate transcription with close ties to RNA polymerase II, and undergo activation, recycling and turnover in a highly orchestrated manner. SMAD proteins are a hub for pathway regulation and compute diverse inputs for a finely tuned response.

  • SMAD proteins recruit a histone reader protein to gain access to repressed chromatin, and histone modifiers, DNA modifiers and nucleosome remodellers to regulate transcription.

  • Master regulators of pluripotency in embryonic stem cells (ES cells) and of lineage determination in progenitor cells dominantly direct signal-activated SMAD proteins to target sites in the genome. In the context of differentiated cells, signal-activated SMAD proteins are directed to different subsets of target genes by different DNA-binding partners.

  • The TGFβ, bone morphogenetic protein (BMP) and WNT pathways converge in the context of ES cells, progenitor cells and cells undergoing epithelial–mesenchymal transition (EMT) or induced pluripotent stem cell (iPS cell) reprogramming. TGFβ kills premalignant cells, and this selects for mutant clones that avert this effect and instead use TGFβ for invasion and metastasis in this context.

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Acknowledgements

The author would like to thank the members of his laboratory for their contributions and critical reading the manuscript. The authors' research in this field is supported by grants from the US National Institutes of Health (NIH).

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  1. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

    • Joan Massagué

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The author declares no competing financial interests.

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Correspondence to Joan Massagué.

Glossary

Myoblasts

Mesenchymal progenitor cells that are committed to differentiate into muscle cells.

Epithelial–mesenchymal transition

(EMT). A phenotypic change that is characteristic of some developing tissues and certain forms of cancer. During EMT, cells lose intercellular junctions and apical–basal polarity, become migratory and, in the case of cancer, become invasive.

Homeobox genes

A family of genes encoding transcription factors that are essential for patterning along the anterior–posterior body axis.

Pro-B cells

Cells in the earliest stage of B cell development in the bone marrow. They are characterized by incomplete immunoglobulin heavy-chain rearrangements and are defined as CD19+ cytoplasmic immunoglobulin M (IgM)− or, sometimes, as B220+CD43+ (according the Hardy classification scheme).

Latent TGFβ complex

A complex that includes a bioactive transforming growth factor-β (TGFβ) dimer non-covalently bound to the cleaved propetide of the TGFβ biosynthetic precursor. This cleavage product in turn covalently binds to latent TGFβ-binding protein (LTBP).

Nucleoporins

Family of proteins that constitute the nuclear pore complex, which is a structure that spans the nuclear envelope in eukaryotic cells.

Polyubiquitylation

Post-translational modification of proteins that involves the covalent attachment and polymerization of ubiquitin moieties to Lys chain amino groups.

WW domains

Protein interaction domains that are found in many proteins. The WW domain is characterized by a pair of Trp residues 20–22 amino acids apart, and an invariant Pro residue within a region of 40 amino acids. WW domains interact with Pro-rich regions, including those containing phospho-Ser or phospho-Thr.

Mediator complex

A multiprotein complex that functions as a transcriptional co-activator and binds to the carboxyterminal domain of the RNA polymerase II (Pol II) holoenzyme. This complex acts as a bridge between the Pol II and transcription factors.

SWI/SNF

(Switch/sucrose nonfermentable). A chromatin-remodelling complex family that was first identified genetically in yeast as a group of genes required for mating type switching and growth on alternative sugar sources to sucrose. This complex is required for the transcriptional activation of 7% of the genome. SWI/SNF complexes exist in multiple forms made up proteins referred to as BRGl-associated factors (BAFs).

MicroRNA

(miRNA). An approximately 21–22 ribonucleotide RNA that arises from the action of the Dicer double-stranded ribonucleases on short stem–loop precursors. miRNAs initiate blocking of the targeted mRNAs, which have nucleotide sequences that are complementary to the miRNA.

Drosha

A ribonuclease III enzyme that initiates processing of microRNAs.

Autocrine

Autocrine signalling refers to when the target cell is the signal-releasing cell itself.

Primitive streak

Structure that forms during early stages of embryonic development. It establishes the first axis of symmetry and marks the beginning of gastrulation.

Melanomas

Malignant tumours derived from melanocyte precursors.

Gliomas

The most common types of malignant tumour in the brain.

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DOI

https://doi.org/10.1038/nrm3434

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