Extracellular Protein Phosphorylation, the Neglected Side of the Modification

The very existence of extracellular phosphorylation has been questioned for a long time, although casein phosphorylation was discovered a century ago. In addition, several modification sites localized on secreted proteins or on extracellular or lumenal domains of transmembrane proteins have been catalogued in large scale phosphorylation analyses, though in most such studies this aspect of cellular localization was not considered. Our review presents examples when additional analyses were performed on already public data sets that revealed a wealth of information about this "neglected side" of the modification. We also sum up accumulated knowledge about extracellular phosphorylation, including the discovery of Golgi-residing kinases and the special difficulties encountered in targeted analyses. We hope future phosphorylation studies will not ignore the existence of phosphorylation outside of the cell, and further discoveries will shed more light on its biological role.