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The ETS-domain transcription factor family

Nature Reviews Molecular Cell Biology volume 2, pages 827–837 (2001)Cite this article

Key Points

  • ETS-domain transcription factors are found in all metazoan organisms and are characterised by the presence of a conserved DNA-binding domain (the ETS-domain). Other domains provide additional functions to each protein, and contribute to their specificity of action at the molecular and biological levels.

  • We now know the structures of several family members that conform to the winged-helix-turn-helix motif. The ETS-domain is also involved in multiple protein-protein interactions in addition to its well defined role in mediating DNA binding.

  • DNA binding is a dynamic process that is tightly regulated. Several ETS-domain proteins are autoinhibited in the absence of inappropriate stimuli or partner proteins. Conversely, such inhibition is lost in the presence of appropriate triggers.

  • ETS-domain proteins bind to a variety of protein partners that inhibit or enhance DNA binding. In addition, they bind to coactivators and corepressors that modulate their transcriptional regulatory properties.

  • Many ETS-domain proteins have been shown to be targeted by MAP-kinase pathways. Phosphorylation by MAP kinases affects DNA binding, transcriptional activation/repression, protein stability and subcellular localisation of different ETS-domain proteins.

  • A major mode of action of ETS-domain transcription factors is to recruit histone acetyl transferases or deacetylases to activate or repress transcription.

  • ETS-domain proteins contribute to a variety of different biological processes. Major themes include roles in haematopoiesis, vasculogenesis and neuronal development. Disruption of these proteins often leads to cancer.

  • It is becoming apparent that many ETS-domain proteins have unique molecular and biological functions. By embracing new technologies, future work is likely to further emphasize this concept and provide us with a unique picture of how individual proteins function.

Abstract

ETS-domain transcription-factor networks represent a model for how combinatorial gene expression is achieved. These transcription factors interact with a multitude of co-regulatory partners to elicit gene-specific responses and drive distinct biological processes. These proteins are controlled by a complex series of inter and intramolecular interactions, and signalling pathways impinge on these proteins to further regulate their action.

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Figure 1: Structure of the ETS domain and pointed domain of Ets-1.
Figure 2: Protein–protein interactions involving the ETS domain.
Figure 3: Regulation of DNA binding by ETS-domain transcription factors.
Figure 4: Structure of the SAP-1–SRF–DNA complex.
Figure 5: Regulation of ETS-domain transcription factors by phosphorylation.
Figure 6: Targeting of the ERK MAPK to Elk-1.

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Acknowledgements

I apologize to colleagues in the field for not referencing all relevant papers owing to space constraints. Where possible, I have indicated the first or most significant papers that illustrate a particular point rather than providing a comprehensive listing. I thank M. Hassler and T. Richmond for help in drawing Fig. 4, and I. Hagan and S.-H. Yang for comments on the manuscript. The author is a research fellow of the Lister Institute of preventive medicine, and research in his lab is funded by the Wellcome Trust, Medical Research Council and Cancer Research Campaign (CRC).

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  1. School of Biological Sciences, University of Manchester, 2.205 Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Andrew D. Sharrocks

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DATABASES

Interpro:

ETS-domain

 Locuslink:

CaMKII

CBP

E74

ERF

Erg

mSin3A

p16

SUMO

TEL

TGF-β type II receptor

Yan

 OMIM:

Ewing sarcoma

 Swiss-Prot:

AML-1

c-myb

ELF1

Elk-1

ER81

EWS

Fli-1

GABPα

Pax-5

PEA3

Pnt

PU.1

SAP-1

SRF

USF-1

v-ets

Glossary

METAZOAN LINEAGE

The eukaryotic phylogenetic lineage that excludes yeasts, fungi and plants.

POINTED DOMAIN

A domain that is conserved in a subset of ETS-domain proteins with homology to the SAM domain and is found in various proteins, such as receptors, protein kinases and adaptor proteins.

WINGED HELIX–TURN–HELIX MOTIF

A subtype of a DNA-binding motif that consists of two α-helices separated by a tight turn. Contains an extended loop between two β-strands (wing) that also contacts DNA.

CAMKII

A protein kinase that is activated in the presence of calcium and the co-regulatory subunit, calmodulin.

ID HELIX–LOOP–HELIX (HLH) PROTEINS

These proteins contain a helix–loop–helix dimerization motif and act as inhibitors of DNA binding by basic HLH transcription factors.

B-BOX

A conserved protein–protein interaction motif that is found in the ternary complex factors that interact with serum response factor.

ANKYRIN REPEATS

These are structural repeat units that consist of two α-helices that form an antiparallel coiled-coil, followed by an extended loop. This was originally identified in ankyrin.

PHOSPHO-ACCEPTOR

An amino acid (typically serine, threonine or tyrosine) that can accept phosphate groups from ATP, which has been catalysed by protein kinases.

HDAC

(histone deacetylase). This catalyses the removal of acetyl groups from proteins.

HAT

(histone acetyltransferase). This catalyses the addition of acetyl groups to proteins.

LYMPHOID AND MYELOID LINEAGES

These are haematopoietic cell lineages that arise from two different progenitor populations.

OSTEOPETROSIS

A weakening of the bones due to the lack of bone matrix.

OSTEOCLASTS

These are cells that are derived from monocyte progenitors on the myeloid lineage that synthesize the bone matrix.

MEGAKARYOCYTIC LINEAGE

This is a haematopoietic cell lineage that arises from the myeloid progenitors that give rise to megakaryocytes and platelets.

SMALL UBIQUITIN-RELATED MODIFIER

(SUMO). A small protein, which is related to ubiquitin, that is conjugated to specific lysine groups in proteins by a complex of proteins.

NEUREGULIN

A growth factor found in neuromuscular synapses that activates members of the epidermal growth factor receptor family.

EXTRACELLULAR MATRIX REMODELLING

The degradation and redeposition of extracellular matrix that allows cell movement and organ growth.

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Sharrocks, A. The ETS-domain transcription factor family. Nat Rev Mol Cell Biol 2, 827–837 (2001). https://doi.org/10.1038/35099076

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