CASK: A Specialized Neuronal Kinase

CASK, a scaffolding protein present in neuronal synapses and other cell junctions, contains a CaM-kinase domain at its N terminus. Due to lack of adequate biochemical data and based on bioinformatics, this domain was classified as a pseudokinase. But new evidence suggests that CASK is a unique kinase which is independent of divalent cofactors. Surprisingly, it is inhibited by many divalent ions which include the essential kinase cofactor magnesium. The inability of CASK to use a cofactor makes it a very slow enzyme; however, this disadvantage of CASK is partially compensated by substrate docking to its scaffolding domains. Indeed, the only characterized substrate to date is Neurexin, which is recruited to CASK via its PDZ domain. Synaptic activity inhibits Neurexin phosphorylation by CASK due to acute influx of divalent ions indicating the divalent ion sensitivity might be a regulatory mechanism. The biological role of this kinase activity remains unclear. It is quite possible that similar to CASK other classified pseudokinases might also turn out to be specialized kinases working in particular physiological niche. Since the discovery of CASK as an active kinase, at least another pseudokinase has turned out to be an active enzyme.