Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity.

Dyrk-related kinases represent a novel subfamily of protein kinases with unique structural and enzymatic features. Its members have been identified in distantly related organisms. The yeast kinase, Yak1, has been characterized as a negative regulator of growth. Mnb from Drosophila is encoded by the minibrain gene, whose mutation results in specific defects in neurogenesis. Its mammalian homolog, Dyrk1A, is activated by tyrosine phosphorylation in the activation loop between subdomains VII and VIII of the catalytic domain. The human gene for Dyrk1A is located in the "Down syndrome critical region" of chromosome 21 and is therefore a candidate gene for mental retardation in Down syndrome. More recently, six additional mammalian Dyrk-related kinases have been identified (Dyrk1B, Dyrk1C, Dyrk2, Dyrk3, Dyrk4A, and Dyrk4B). All members of the Dyrk family contain in the activation loop the tyrosines that are essential for the full activity of Dyrk1A. Outside their catalytic domains, Dyrk kinases exhibit little sequence similarity except for a small segment immediately preceding the catalytic domain (DH-box, Dyrk homology box). An unusual enzymatic property of Dyrk-related kinases is their ability to catalyze tyrosine-directed autophosphorylation as well as phosphorylation of serine/threonine residues in exogenous substrates. The exact cellular function of the Dyrk kinases is yet unknown. However, it appears reasonable to assume that they are involved in the regulation of cellular growth and/or development.