Review
Ternary complex factors: prime nuclear targets for mitogen-activated protein kinases

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Abstract

Ternary complex factors (TCFs), a subgroup of the ETS protein family, were first described in the context of c-fos gene regulation. Subsequently, their early identification as nuclear targets for mitogen-activated protein kinases served to exemplify the fundamental links in eukaryotic cells between growth factor-mediated signalling pathways and gene control.

This article provides an overview of recent work on ternary complex factors, addressing their expression and molecular structure, as well as how selective interactions with members of other protein families serve to up-1 regulate or restrict their activity. Although only one genetic study on ternary complex factors has been published to date, unravelling of the underlying molecular events provides a basis for tentative predictions about their biological roles in mammalian organisms.

Introduction

More than a decade has passed since the activity of a transcription factor, now known to be that of a sub-group of ETS proteins referred to as ternary complex factors (TCFs), was first characterised in the context of c-fos gene regulation. The intervening years have seen TCFs become inextricably linked to gene control by growth signals and, to a lesser extent, cellular stress, as their activity was shown to be up-regulated by mitogen-activated protein kinase (MAPK) cascades. Although a complete understanding of their molecular function is still an aspiration, it is nonetheless apparent that TCFs provide a powerful model to probe eukaryotic gene control. In addition, an interpretation of their biological roles in higher eukaryotes can be inferred from the available clues. This review aims to present the recent advances in our understanding of TCF structure and function.

Section snippets

Expression of TCFs

The name ETS derives from the E26 acute leukaemia virus and was first used to denote a novel oncogene in the viral genome. There are now over 45 mammalian ETS proteins known, deriving from at least 22 different genes (Laudet, Hänni, Stéhelin, & Duterque-Coquillaud, 1999). Three of the genes encode TCFs: elk-1, which was cloned and described over 10 years ago albeit in a different context (Hipskind, Rao, Mueller, Reddy, & Nordheim, 1991; Rao et al., 1989), and those for Sap1a (Dalton & Treisman,

Molecular structure of TCFs

ETS proteins share a characteristic ‘winged helix-turn-helix’ DNA-binding domain (Brennan, 1993). The first structures to be solved were those of Fli-1, Ets-1 and PU.1 in complex with DNA (Kodandapani et al., 1996, Liang et al., 1994, Werner et al., 1995). In addition, the ETS domain structures of both Sap1a and Elk-1 have been elucidated (Mo, Vaessen, Johnston, & Marmorstein, 1998; Mo, Vaessen, Johnston, & Marmorstein, 2000). The domain inserts an α-helix (α3) into the major groove of the DNA,

Truncated TCFs

A body of evidence describes truncated TCFs that lack amino acids to various degrees (see Fig. 2). Two C-terminally truncated versions of Net have been described, Net-b and Net-c (Giovane, Sobieszczuk, Ayadi, Maira, & Wasylyk, 1997). In NIH3T3 fibroblasts and 70Z/3 pre-B cells Net-b appears to be expressed at similar levels to full-length Net whereas endogenous Net-c expression could not be detected. Net-b forms ternary complexes with SRF but lacks a trans-activation domain, consistent with its

Activation of TCFs

That TCFs are substrates for MAPKs was first demonstrated with purified native protein fractions, consisting of ERK1 and p62TCF/Elk-1 isolated from HeLa cells, whereby phosphorylation was shown to stimulate ternary complex formation with SRF (Gille, Sharrocks, & Shaw, 1992). Subsequently transcriptional activation by Elk-1 was shown to depend on the integrity of several consensus sites in the carboxy-terminal domain of Elk-1 that are rapidly phosphorylated following mitogen stimulation of cells

TCF–MAPK complexes

A body of evidence supports the notion that TCFs are activated differentially by the three MAPK cascades. Given its absolute requirement for a Ras-dependent stimulus, only one component of which is MAPK activation, the distinction between Net and the other two TCFs is profound (Giovane et al., 1994; Price & Rogers, 1995). However, in spite of some contradictory reports, more subtle differences have also been detected between Elk-1 and Sap1a. A range of stress agonists including UV-light,

Autonomous DNA binding versus ternary complex formation

Whether the role of mammalian TCFs is exclusively that of accessory factors to SRF or to other transcription factors is a moot point. It is clear that autonomous DNA binding by TCFs is manifested under some conditions. For example, a sequence motif from the Drosophila melanogaster E74 gene, which encodes two ETS proteins involved in metamorphosis (Burtis, Thummel, Jones, Karim, & Hogness, 1990), serves in vitro as a high-affinity binding site for TCFs and, when multimerised, mediates

Transcriptional regulation by TCFs

Despite intensive study, the mechanism by which TCFs stimulate transcriptional initiation remains poorly understood. Of the factors known to constitute the basal transcription machinery, the RNA polymerase II holoenzyme or chromatin remodelling engines, little is known about their ability to interact with the carboxy-terminal trans-activation domains of TCFs. One candidate co-activator is the CREB-binding protein (CBP/p300) (Chan & La Thangue, 2001). Both Elk-1 and Sap1a have been shown to

Biological role of TCFs

In general terms, two classes of data provide indications of the roles played by TCFs. On the one hand, a large number of studies has been performed to assess the effects of natural and synthetic agonists on intracellular signal transduction pathways and gene expression, and activation of TCFs, to some extent victims of their efficacy as MAPK targets, has been a common parameter of study. In this way a picture of TCFs as mediators of gene expression in response to a range of stimuli has

Perspective

Although a tremendous amount of information on TCFs has been forthcoming, our understanding of their function is still far from complete. The most pressing issues are to elucidate the complete molecular structure of the ternary complex, to understand the changes induced by TCF phosphorylation and to identify the interaction partners required by TCFs to achieve the characteristically rapid and efficient stimulation of transcription. Beyond that, the roles for Elk-1 and Sap1a in the context of

Acknowledgments

Thanks are due to Stephen Doughty, for generating the images of the ternary complex, to Peter Jones and Francisco Cruzalegui for comments on the manuscript and to Wendy Solis for help with its preparation. The authors’ research is funded by the AICR, BBSRC, Servier and the Wellcome Trust.

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