Does isoform diversity explain functional differences in the 14-3-3 protein family?

The 14-3-3 family of proteins was originally identified in 1967 as simply an abundant brain protein. However it took almost 25 years before the ubiquitous role of 14-3-3 in cell biology was recognized when it was found to interact with several signalling and proto-oncogene proteins. Subsequently 14-3-3 proteins were the first protein recognized to bind a discrete phosphoserine/threonine-binding motifs. In mammals the 14-3-3 protein family is comprised of seven homologous isoforms. The 14-3-3 family members are expressed in all eukaryotes and although no single conserved function of the 14-3-3s is apparent, their ability to bind other proteins seems a crucial characteristic. To date more than 300 binding partners have been identified, of which most are phosphoproteins. Consequently, it has become clear that 14-3-3 proteins are involved in the regulation of most cellular processes, including several metabolic pathways, redox-regulation, transcription, RNA processing, protein synthesis, protein folding and degradation, cell cycle, cytoskeletal organization and cellular trafficking. In this review we include recent reports on the regulation of 14-3-3 by phosphorylation, and discuss the possible functional significance of the existence of distinct 14-3-3 isoforms in light of recent proteomics studies. In addition we discuss 14-3-3 interaction as a possible drug target.