|Abstract:Protein phosphatases are the essential opposite to protein kinases; together, these enzymes regulate all protein phosphorylation and most cellular processes. To better understand the global roles of protein phosphorylation, we cataloged the human protein phosphatome, composed of 189 known and predicted human protein phosphatase genes. We also identified 79 protein phosphatase pseudogenes or retrogenes, some of which may have residual function. We traced the origin and diversity of phosphatases by building protein phosphatomes for eight other eukaryotes, from the protist Dictyostelium to the sea urchin. We classified protein phosphatases from all nine species into a hierarchy of 10 protein folds, 21 families, and 178 subfamilies. We found that >80% of the 101 human subfamilies were conserved across the animal kingdom, but show substantial differences in evolution, including losses and expansions of individual subfamilies and changes in accessory domains. Protein phosphatases show similar evolutionary dynamics to those of kinases, with substantial losses in major model organisms. Sequence analysis predicts that 26 human protein phosphatase domains are catalytically disabled and that this disability is mostly conserved across orthologs. This genomic and evolutionary perspective on protein phosphatases provides a framework for global analysis of protein phosphorylation throughout the animal kingdom.