Proteolytic signaling: An introduction

Proteases account for almost 2% of every known genome and are ubiquitously required by different signaling pathways in living organisms. Unlike signaling pathways in which some reactions may be reverted by enzymes acting in opposing reactions, such as pathways regulated by kinases and phosphatases, the uniqueness of proteolytic signaling is mainly related to its irreversibility: proteases hydrolyze substrates, thereby resulting in the physical separation of portions in target proteins. Furthermore, limited proteolysis increases protein diversity both structurally and functionally, thereby also increasing the biological reachability of input signals in biological circuits. Hence, proteolytic signaling can be described as a biological signaling event that is not only triggered and regulated by proteolysis; it is a signaling pathway, in which the cleavage event may significantly affect the fate of target proteins and, more importantly, the biological outcome. Therefore, proteolytic signaling must be understood in light of the fate of processed substrates and their corresponding roles in biological circuits—the slight imbalance in protease web may answer for substantial deviations from health to disease states.