Specificity of cellular signaling scaffolds

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14-3-3 proteins comprise a family of highly conserved and abundant regulatory molecules. They interact with a large number of target (client) proteins in a phosphorylation-dependent manner. By so doing, they are critical components of most eukaryotic signaling pathways. 14-3-3 clients are structurally and functionally highly diverse. They are involved in e.g. cell cycle, apoptosis, DNA damage, transcription, and cell motility. Intriguingly, the exact mode of action of 14-3-3 proteins varies depending on the client protein. They can regulate their clients’ enzymatic activity, conformation, assembly into complexes, subcellular localization, or mediate aggregation. Consequently, 14-3-3s represent an unusually versatile regulatory platform for signaling in eukaryotes.