14-3-3 Proteins: Active Cofactors in Cellular Regulation by Serine/Threonine Phosphorylation

Abstract

The 14-3-3 proteins are a family of abundant, widely expressed 28–33-kDa acidic polypeptides that spontaneously self-assemble as dimers. The 14-3-3 proteins were first detected by virtue of their relatively high abundance in brain extracts and given their unique name (an unfailing source of curiosity) based on their fraction number on DEAE-cellulose chromatography and migration position on starch gel electrophoresis (1). One or another 14-3-3 iso- forms was repeatedly rediscovered in association with proteins of biologic interest; however, the functions of these polypeptides re- mained speculative until the demonstration by Shaw and col-leagues (2) that 14-3-3 proteins bind to phosphoserine-containing motifs in a sequence-specific manner. This insight enabled a sys-tematic approach to understanding the functional roles of the 14- 3-3 proteins and was followed by the demonstration that the 14-3-3 proteins participate in a wide range of biologic processes acting through a variety of regulatory mechanisms mediated mostly, and perhaps exclusively, through their binding to phosphoserine-con- taining sequence motifs in diverse partners (for review see Refs. 3–9). Other sequence-specific phosphoserine/phosphothreonine- binding domains have been subsequently defined with differing target specificity (Table I) such as WW domains, FHA domains, and WD40 and LRR domains of F-box proteins (reviewed in Refs. 10– 12), complementing the previously defined phosphotyrosine-bind- ing, SH 2 and PTB domains.