The Dark Side of Cell Signaling: Positive Roles for Negative Regulators

Cell signaling is dominated by analyzing positive responses to stimuli. Signal activation is balanced by negative regulators that are generally considered to terminate signaling. Rather than exerting only negative effects, however, many such regulators play important roles in enhancing cell-signaling control. Considering responses downstream of selected cell-surface receptors, we discuss how receptor internalization affects signaling specificity and how rapid kinase/phosphatase and GTP/GDP cycles increase responsiveness and allow kinetic proofreading in receptor signaling. We highlight the blurring of distinctions between positive and negative signals, recasting signal termination as the response to a switch-like transition into a new cellular state.