All intrinsically active Erk1/2 mutants autophosphorylate threonine207/188, a plausible regulator of the TEY motif phosphorylation

Alexey Baskin, Nadine Soudah, Nechama Gilad, Neriya Halevi, Ilona Darlyuk-Saadon, Hanan Schoffman, David Engelberg

Research output: Contribution to journalArticlepeer-review

Abstract

The extracellular-activated kinases 1 & 2 (Erk1/2) are catalytically active when dually phosphorylated on a TEY motif located at the activation loop. In human patients with cardiac hypertrophy, Erk1/2 are phosphorylated on yet another activation loop's residue, T207/188. Intrinsically active variants of Erk1/2, mutated at R84/65, are also (auto)phosphorylated on T207/188. It is not known whether T207/188 phosphorylation is restricted to these cases, nor how it affects Erks' activity. We report that T207/188 phosphorylation is not rare, as we found that: 1) All known auto-activated Erk1/2 variants are phosphorylated on T207/188. 2) It occurs in various cell lines and mouse tissues. 3) It is extremely high in patients with skeletal muscle atrophies or myopathies. We propose that T207/188 controls the permissiveness of the TEY motif for phosphorylation because T207/188-mutated Erk1/2 and the yeast Erk/Mpk1 were efficiently dually phosphorylated when expressed in HEK293 or yeast cells, respectively. The T207/188-mutated Mpk1 was not TEY-phosphorylated in cells knocked out for MEKs, suggesting that its enhanced phosphorylation in wild-type cells is MEK-dependent. Thus, as T207/188-mutated Erk1/2 and Mpk1 recruit MEKs, the role of T207/188 is to impede MEKs' ability to phosphorylate Erks. T207/188 also impedes autophosphorylation as recombinant Erk2 mutated at T188 is spontaneously autophosphorylated, although exclusively on Y185. The role of T207/188 in regulating activation loop phosphorylation may be common to most Ser/Thr kinases, as 86% of them (in the human kinome) possess T207/188 orthologs, and 160 of them were already reported to be phosphorylated on this residue.

Original languageEnglish
Article number108509
JournalJournal of Biological Chemistry
Volume301
Issue number6
DOIs
StatePublished - Jun 2025

Keywords

  • Erk
  • MAP kinases
  • TEY motif
  • activation loop
  • eukaryotic protein kinases (EPKs)
  • myopathy
  • phosphorylation
  • skeletal muscle atrophy

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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