Nuclear ERK translocation is mediated by protein kinase CK2 and accelerated by autophosphorylation

Alexander Plotnikov, Dana Chuderland, Yael Karamansha, Oded Livnah, Rony Seger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background/Aims: The extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase (MAPK) family. Upon stimulation, these kinases translocate from the cytoplasm to the nucleus, where they induce physiological processes such as proliferation and differentiation. The mechanism of translocation of this kinase involves phosphorylation of two Ser residues within a nuclear translocation signal (NTS), which allows binding to importin7 and a subsequent penetration via nuclear pores. However, the regulation of this process and the protein kinases involved are not yet clear. Methods: To answer this point we developed specific anti phospho-SPS antibody, used this and other antibodies in Western blots and crystalized the phospho-mimetic mutated ERK. Results: Here we show that the phosphorylation of both Ser residues is mediated mainly by casein kinase 2 (CK2) and that active ERK may assist in the phosphorylation of the N-terminal Ser. We also demonstrate that the phosphorylation is dependent on the release of ERK from cytoplasmic anchoring proteins. Crystal structure of the phosphomimetic ERK revealed that the NTS phosphorylation creates an acidic patch in ERK. Our model is that in resting cells ERK is bound to cytoplasmic anchors, which prevent its NTS phosphorylation. Upon stimulation, phosphorylation of the ERK TEY domain releases ERK and allows phosphorylation of its NTS by CK2 and active ERK to generate a negatively charged patch in ERK, binding to importin 7 and nuclear translocation. Conclusion: These results provide an important role of CK2 in regulating nuclear ERK activities.

Original languageAmerican English
Pages (from-to)366-387
Number of pages22
JournalCellular Physiology and Biochemistry
Volume53
Issue number2
DOIs
StatePublished - 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s).

Keywords

  • CK2
  • ERK
  • Importin7
  • MAPK
  • Nuclear translocation

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