DYRK, A DUAL-SPECIFICITY PROTEIN-KINASE WITH UNIQUE STRUCTURAL FEATURES WHOSE ACTIVITY IS DEPENDENT ON TYROSINE RESIDUES BETWEEN SUBDOMAIN-VII AND SUBDOMAIN-VIII

The cDNA of a novel, ubiquitously expressed protein kinase (Dyrk) was cloned from a rat brain cDNA library, The deduced amino acid sequence (763 amino acids) contains a catalytic domain that is only distantly r elated to that of other mammalian protein kinases, Its closest relativ e is the protein kinase Mnb of Drosophila, which is presumably involve d in postembryonic neurogenesis (85% identical amino acids within the catalytic domain). Outside the catalytic domain, the sequence comprise s several striking structural features: a bipartite nuclear translocat ion signal, a tyrosine-rich hydrophilic motif flanking the nuclear loc alization signal, a PEST region, a repeat of 13 histidines, a repeat o f 17 serine/threonine residues, and an alternatively spliced insertion of nine codons, A recombinant glutathione S-transferase-Dyrk fusion p rotein catalyzed autophosphorylation and histone phosphorylation on ty rosine and serine/threonine residues with an apparent K-m of approxima tely 3.4 mu M. Exchange of two tyrosine residues in the ''activation l oop'' between subdomains VII and VIII for phenylalanine almost complet ely suppressed the activity and tyrosine autophosphorylation of Dyrk, Tyrosine autophosphorylation was also reduced by exchange of the tyros ine (Tyr-219) in a tyrosine phosphorylation consensus motif, The data suggest that Dyrk is a dual specificity protein kinase that is regulat ed by tyrosine phosphorylation in the activation loop and might be a c omponent of a signaling pathway regulating nuclear functions.