The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2B? at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase

摘要

pThe substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Sersup535/sup. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Sersup535/sup if Sersup539/sup is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Sersup539/sup have so far been identified. Here we show that Sersup539/sup of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of bd/bual-specificity tby/brosine phosphorylated and br/begulated bk/binase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Sersup539/sup permits GSK3 to phosphorylate Sersup535/supiin vitro/i and that eIF2Bε is highly phosphorylated at Sersup539/supiin vivo/i. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thrsup212/supiin vitro/i, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer9s-disease brain. Phosphorylation of Thrsup212/sup primes tau for phosphorylation by GSK3 at Sersup208/supiin vitro/i, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates./p