The kinase DYRK phosphorylates protein-synthesis initiation factor elF2Bε at Ser539 and the microtubule-associated protein tau at Thr212: Potential role for DYRK as a glycogen synthase kinase 3-priming kinase

Yvonne L. Woods, Philip Cohen, Walter Becker, Ross Jakes, Michel Goedert, Xuemin Wang, Christopher Proud

Research output: Contribution to journalArticle

204 Citations (Scopus)

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 ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε 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 eIF2Bε, 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 eIF2Bε 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.

LanguageEnglish
Pages609-615
Number of pages7
JournalBiochemical Journal
Volume355
Issue number3
DOIs
Publication statusPublished - 1 May 2001

Keywords

  • Alzheimer's disease
  • Down's syndrome
  • Insulin action
  • Protein phosphorylation
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "The kinase DYRK phosphorylates protein-synthesis initiation factor elF2Bε at Ser539 and the microtubule-associated protein tau at Thr212: Potential role for DYRK as a glycogen synthase kinase 3-priming kinase",
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 ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε 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 eIF2Bε, 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 eIF2Bε 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.",
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The kinase DYRK phosphorylates protein-synthesis initiation factor elF2Bε at Ser539 and the microtubule-associated protein tau at Thr212 : Potential role for DYRK as a glycogen synthase kinase 3-priming kinase. / Woods, Yvonne L.; Cohen, Philip; Becker, Walter; Jakes, Ross; Goedert, Michel; Wang, Xuemin; Proud, Christopher.

In: Biochemical Journal, Vol. 355, No. 3, 01.05.2001, p. 609-615.

Research output: Contribution to journalArticle

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T1 - The kinase DYRK phosphorylates protein-synthesis initiation factor elF2Bε at Ser539 and the microtubule-associated protein tau at Thr212

T2 - Biochemical Journal

AU - Woods, Yvonne L.

AU - Cohen, Philip

AU - Becker, Walter

AU - Jakes, Ross

AU - Goedert, Michel

AU - Wang, Xuemin

AU - Proud, Christopher

PY - 2001/5/1

Y1 - 2001/5/1

N2 - 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 ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε 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 eIF2Bε, 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 eIF2Bε 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.

AB - 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 ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε 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 eIF2Bε, 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 eIF2Bε 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.

KW - Alzheimer's disease

KW - Down's syndrome

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