Kinase for secreted proteins found
May 10, 2012 § 1 Comment
You may think that all important kinases had been discovered by now. But a paper fresh on the Science Express site reminds us that there is still much left to be understood about molecular biology. This paper describes the discovery of a kinase family that phosphorylates secreted proteins.
Most phosphorylated proteins stay inside cells, but some are secreted. But which kinase phosphorylates these secreted extracellular proteins has remained elusive. A team including Jack E. Dixon and Vincent Tagliabracci at the University of California, San Diego, and Nick Grishin at University of Texas Southwestern Medical Center at Dallas found a family of protein kinases that localize within the Golgi apparatus. Some of these kinases are secreted from the cell.
Why has this kinase family been so elusive? “The kinase does not have all of the key conserved residues that are seen in the traditional kinases, so a BLAST search does not turn up this family,” explains Dixon. He adds the kinase is in the lumen of the Golgi, a location where traditional kinases aren’t found. They are usually in the cytoplasm.
In particular, the investigators identified Fam20C as the kinase that phosphorylates secreted proteins such as casein and proteins involved in biomineralization.
As Dixon and colleagues note in their paper, casein has been known to be phosphorylated since 1883 and is widely used as a test substrate to discover new kinases and monitor their activities. But no one to date has actually molecularly characterized the kinase that phosphorylates casein.
Casein kinase activity has been found in Golgi fractions isolated from lactating mammary glands, liver, brain and kidney. It phosphorylates the serine in the amino acid sequence S-X-E/pS, where X is any amino acid and E/pS is glutamate or phosphoserine already phosphorylated by a different kinase.
Dixon and colleagues showed that Fam20C phosphorylates a number of secreted proteins on this motif. Its substrates include proteins important for bone development such as osteopontin, dentin matrix protein-1 and bone sialoprotein. They all contain the S-X-E/pS motif. The role of phosphorylation in many of these proteins remains a big question.
However, it was previously known that mutations in this kinase activity results in Raine syndrome, a rare disease in humans that causes major craniofacial defects. Children with Raine syndrome usually only survive a few hours after birth. “It suggests the kinase activity of FAM 20C is required for normal development of bone as well as other tissues,” says Dixon.
Dixon served as president of the American Society for Biochemistry and Molecular Biology in 1996. Since 2007, he has been vice president and chief scientific officer at the Howard Hughes Medical Institution. HHMI announced earlier this week that Dixon will retire from the post in 2013.