Multisite phosphorylation provides a reliable mechanism for making decisions in noisy environments

The ability to make decisions at the cellular level is absolutely critical for the survival of organisms. Eukaryotic cells are constantly making binary decisions in response to internal and environmental signals. Among the most notable transducers of information are protein kinases. The regulation of these signaling proteins often relies on the activity of other protein kinases located upstream in the signaling cascade. However, these signaling systems are by their own nature an important source of molecular noise. Herein, we have assessed the role of multisite phosphorylation in detecting signals in the face of molecular noise. To address this issue, we have conceptually envisioned the biochemical transduction machinery as a classifier model that can lead to four possible outputs: true positives and negatives, and false positives and negatives. In this probabilistic framework, we show that multisite phosphorylation represents a mechanism to filter noise during the decision‐making process. We present results showing that nonessential phosphorylation sites contribute to increase the rate of true positives while, at the same time, they can lessen the rate of false positives. This simultaneous increase in sensitivity and specificity, makes multisite phosphorylation a valuable and easily implemented mechanism to reliably transduce information in noisy contexts.