The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2B epsilon at Ser(539) and the microtubule-associated protein tau at Thr(212): potential role for DYRK as a glycogen synthase kinase 3-priming kinase

Woods, Y.L., Cohen, P., Becker, W., Jakes, R., Goedert, M., Wang, X.M. and Proud, C.G. (2001) The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2B epsilon at Ser(539) and the microtubule-associated protein tau at Thr(212): potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochemical Journal, 355 (3), 609-615.

Abstract

The 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 e-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Be), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Be at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Be, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other 'proline-directed' protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535 in vitro and that eIF2Be is highly phosphorylated at Ser539 in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212 in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208 in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.

This record has no associated files available for download.

Contributors

Download statistics