A hallmark of signal transduction pathways is the reversible phosphorylation of serine and threonine residues within specific sequences, or motifs, in target proteins. Specific signaling motifs include not only sequences that are recognized by protein kinases, but also those that are recognized by phosphorylation-dependent binding proteins like 14-3-3. These modular phosphoprotein interacting domains are critical elements in modulating, directing and amplifying intracellular communications. Many critical protein kinases can be regulated by phosphorylation at a specific serine or threonine surrounded by phenylalanine or tyrosine. For example, Akt, an important kinase that regulates cell survival, is activated by phosphorylation at Ser473, a site surrounded by phenylalanine and tyrosine. RSK1, p70S6K, and certain PKC isoforms also contain a similar consensus phosphorylation site. Phosphorylation of these sites is required for kinase activity.