Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome

Cellular and Molecular Life Sciences : CMLS
Anne L AshfordSimon J Cook

Abstract

The dual-specificity tyrosine-phosphorylation-regulated kinase, DYRK1B, is expressed de novo during myogenesis, amplified or mutated in certain cancers and mutated in familial cases of metabolic syndrome. DYRK1B is activated by cis auto-phosphorylation on tyrosine-273 (Y273) within the activation loop during translation but few other DYRK1B phosphorylation sites have been characterised to date. Here, we demonstrate that DYRK1B also undergoes trans-autophosphorylation on serine-421 (S421) in vitro and in cells and that this site contributes to DYRK1B kinase activity. Whilst a DYRK1B(S421A) mutant was completely defective for p-S421 in cells, DYRK1B inhibitors caused only a partial loss of p-S421 suggesting the existence of an additional kinase that could also phosphorylate DYRK1B S421. Indeed, a catalytically inactive DYRK1B(D239A) mutant exhibited very low levels of p-S421 in cells but this was increased by KRAS(G12V). In addition, selective activation of the RAF-MEK1/2-ERK1/2 signalling pathway rapidly increased p-S421 in cells whereas activation of the stress kinases JNK or p38 could not. S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro....Continue Reading

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Citations

Mar 13, 2019·International Journal of Molecular Sciences·Galia Maik-RachlineRony Seger
Jul 3, 2020·Proceedings of the National Academy of Sciences of the United States of America·Chao DongMichael S Y Huen
May 29, 2020·Cellular and Molecular Life Sciences : CMLS·Alejandro Correa-SáezMarco A Calzado
Jan 29, 2021·World Journal of Stem Cells·Nikolaos Kokkorakis, Maria Gaitanou
Aug 8, 2021·Cell Death and Differentiation·Maribel Lara-ChicaMarco A Calzado

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
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transfection
flow cytometry
transfections

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