TY - JOUR
T1 - All intrinsically active Erk1/2 mutants autophosphorylate threonine207/188, a plausible regulator of the TEY motif phosphorylation
AU - Baskin, Alexey
AU - Soudah, Nadine
AU - Gilad, Nechama
AU - Halevi, Neriya
AU - Darlyuk-Saadon, Ilona
AU - Schoffman, Hanan
AU - Engelberg, David
N1 - Publisher Copyright: © 2025 The Authors
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - Erk
KW - MAP kinases
KW - TEY motif
KW - activation loop
KW - eukaryotic protein kinases (EPKs)
KW - myopathy
KW - phosphorylation
KW - skeletal muscle atrophy
UR - http://www.scopus.com/inward/record.url?scp=105004817603&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2025.108509
DO - 10.1016/j.jbc.2025.108509
M3 - مقالة
C2 - 40222547
SN - 0021-9258
VL - 301
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
M1 - 108509
ER -