Review
14-3-3 proteins: A historic overview

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Abstract

This chapter includes a historic overview of 14-3-3 proteins with an emphasis on the differences between potentially cancer-relevant isoforms on the genomic, protein and functional level. The focus will therefore be on mammalian 14-3-3s although many important developments in the field have involved Drosophila 14-3-3 proteins for example and the cross-fertilisation from parallel studies on plant 14-3-3 should not be underestimated. In the major part of this review I will attempt to focus on some novel data and aspects of 14-3-3 structure and function, in particular regulation of 14-3-3 isoforms by oncogene-related protein kinase phosphorylation and aspects of 14-3-3 research with which newcomers to the field may be less familiar.

Introduction

Members of the 14-3-3 protein family form a group of highly conserved 30 kDa acidic proteins expressed in a wide range of organisms and tissues. The five major mammalian brain 14-3-3 isoforms are named α–η after their respective elution positions on HPLC [1], [2]. α and δ are the phosphoforms of β and ζ, respectively [3]. Two other isoforms τ (also known as θ) and σ are expressed in T cells and epithelial cells, respectively, although the former is also widely expressed in other tissues including brain. 14-3-3 is now established as a family of dimeric proteins that can modulate interaction between proteins (including oncogene products of polyoma middle T, Raf-1, AKT and Bcr-Abl). They are involved in cell signalling, regulation of cell cycle progression, intracellular trafficking/targeting, cytoskeletal structure and transcription. In many cases, the interacting proteins show a distinct preference for a particular isoform(s) of 14-3-3. A specific repertoire of dimer formation may influence which of the 14-3-3 interacting proteins could be brought together. The regulation of interaction usually involves phosphorylation of the interacting protein and in some cases the phosphorylation of 14-3-3 isoforms themselves may modulate interaction.

Section snippets

Discovery and name

The name 14-3-3 was given to an abundant mammalian brain protein family due to its particular elution and migration pattern on two-dimensional DEAE-cellulose chromatography and starch gel electrophoresis [4]. The 14-3-3 proteins elute in the 14th fraction of bovine brain homogenate from the authors’ “homemade” DEAE cellulose column and fractions 3.3 in the latter step. Members of the family have been given many other names when they have been rediscovered by other researchers due to their

Occurrence of 14-3-3 family and sequence conservation

The 14-3-3 family is highly conserved over a wide range of mammalian species, where the individual isoforms, β, ɛ, η, γ, τ (also called θ), ζ and σ are largely identical, but contain a few regions of diversity. Homologues of 14-3-3 proteins have also been found in a broad range of eukaryotic organisms and are probably ubiquitous (reviewed in [30], [31]). In almost every known organism, multiple (at least two) isoforms of 14-3-3 have been observed [32] and at least 12 (probably 15) isoforms are

Structures of 14-3-3 dimers and their interactions

The first 14-3-3 structures to be determined were the τ and ζ isoforms [39], [40]. These studies showed that they are highly helical, dimeric proteins. Each monomer is composed of nine antiparallel α-helices, organised into an N-terminal and a C-terminal domain. The dimer creates a large negatively charged channel. Those regions of the 14-3-3 protein, which are invariant throughout all the isoforms are mainly found lining the interior of this channel, while the variable residues are located on

The 14-3-3 binding motif

Muslin et al. [50] demonstrated that a novel phosphoserine containing motif initially identified in Raf kinase was important for interaction, and showed that target protein phosphorylation is important for 14-3-3 binding. The motif was further refined into two sub-types: RSXpSXP (mode I) and RXY/FXpSXP (mode II) [51] where pS is phosphoserine. There are also six known interacting proteins with a novel carboxy terminal, -pS/pT X1-2-CO2 H “mode III” motif (where X is not Pro) [52]. Novel roles

Phosphorylation of 14-3-3 isoforms

The regulation of interaction with 14-3-3 through phosphorylation of the target protein is now well established and many reviews have been published on the subject [[64], [65] and this issue]. Recently, it is also becoming clear that the phosphorylation of 14-3-3 isoforms on specific residues (summarised in Fig. 1) has an important regulatory role—in this case by preventing interaction. A number of examples of the regulation of large signalling complexes by are shown in Fig. 2A and B. This

Non-phosphorylated and novel 14-3-3 binding motifs

Some well-characterised interacting proteins such as Raf kinase have been shown to have additional binding site(s) for 14-3-3 on their cysteine-rich regions. Bcr also binds via a serine-rich region.

Along with several other 14-3-3 binding proteins, Exoenzyme S (ExoS), the ADP-ribosyltransferase toxin secreted by the bacterium Pseudomonas aeruginosa, interacts with 14-3-3 in a phosphorylation-independent mechanism [85]. The DALDL sequence in ExoS (residues 424–428 at the C-terminus) that is

Summary/conclusions

Many names have been ascribed to 14-3-3 proteins, depending on the discoverers of a particular novel role (Table 1). However, the name “14-3-3” is well established now and the name is functionally neutral. This may well be an advantage given that members of the family are now known to have so many diverse roles, across the whole eukaryote phyla (and since 14-3-3 also interacts with other biomolecules including DNA) [15]. The accumulated literature on 14-3-3 over the past few years shows how

Acknowledgement

The work in the author's laboratory was supported by the Medical Research Council, EU and Wellcome Trust.

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