Since the discovery of protein kinases, protein phosphorylation has emerged as a key regulatory mechanism. The majority of phosphoproteins reside within the nucleus and cytoplasm; however, many secreted proteins are phosphorylated by unknown kinases located within the secretory pathway and/or in the extracellular space. The Fam20 kinases are emerging as the enzymes responsible for phosphorylating secreted proteins and proteoglycans. Evolutionary analysis reveals that these kinases are exclusively present in metazoans and contain conserved features that are common among all eukaryotic protein kinases. Mutations in the Fam20 family members cause disorders of biomineralization in humans that highlight the physiological significance of secreted protein phosphorylation.

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