Extracellular phosphorylation and phosphorylated proteins: not just curiosities but physiologically important

Mining of the literature and high-throughput mass spectrometry data from both healthy and diseased tissues and from body fluids reveals evidence that various extracellular proteins can exist in phosphorylated states. Extracellular kinases and phosphatases (ectokinases and ectophosphatases) are active in extracellular spaces during times of sufficiently high concentrations of adenosine triphosphate. There is evidence for a role of extracellular phosphorylation in various physiological functions, including blood coagulation, immune cell activation, and the formation of neuronal networks. Ectokinase activity is increased in some diseases, including cancer, Alzheimer's disease, and some microbial infections. We summarize the literature supporting the physiological and pathological roles of extracellularly localized protein kinases, protein phosphatases, and phosphorylated proteins and provide an analysis of the available mass spectrometry data to annotate potential extracellular phosphorylated proteins.