Fam20 structure is shown as ribbons. The N- and C-lobes are shown in magenta and teal, respectively.  The alpha helix (PKA aC equivalent) is highlighted in orange.  The N-terminal segment, the insertion domain, and the C-terminal extension are in white.

In eukaryotes, most phosphoproteins reside within the nucleus and cytosol.  However, extracellular proteins, such as the milk protein casein, are also phosphorylated by “orphan” kinases located within the secretory pathway.  In fact, the first evidence alluding to the existence of protein kinases dates back to the nineteenth century when Olof Hammarsten detected phosphorous in casein.  In hindsight, this was the first indication for the existence of protein kinases that were ultimately discovered and named nearly one century later using casein as a model substrate.  

The Dixon lab has recently identified a family of atypical “secreted” kinases that constitute a novel branch within the human kinome tree.  The Fam20-family of kinases appears to be responsible for the phosphorylation of extracellular proteins and proteoglycans.  What defines these kinases is the presence of a signal peptide that directs these enzymes to the secretory pathway where phosphorylation of ER/Golgi resident proteins, extracellular domains of cell surface receptors, xylose residues within the glycosaminoglycan-protein linkage and secreted proteins occurs.  

The proteins known as "casein kinases" are in fact cytosolic and nuclear proteins and do not mediate physiological phosphorylation of casein because they are spatially restricted from the secretory apparatus and the extracellular space.  We have discovered that Fam20C phosphorylates the caseins and several secreted proteins implicated in biomineralization, including the small integrin binding ligand, N-linked glycoproteins (SIBLINGs).  Consequently, mutations in Fam20C cause a devastating osteosclerotic bone dysplasia in humans known as Raine syndrome.