Modulation of the eIF2α kinase PERK by tyrosine phosphorylation

The endoplasmic reticulum (ER)-resident protein kinase
PERK attenuates protein synthesis in response to ER stress
through the phosphorylation of translation initiation factor
eIF2a at serine 51. ER stress induces PERK autophosphorylation
at several serine/threonine residues, a process that is
required for kinase activation and phosphorylation of eIF2a.
Herein, we demonstrate that PERK also possesses tyrosine
kinase activity. Specifically, we show that PERK is capable of
autophosphorylating on tyrosine residues in vitro and in vivo.
We further show that tyrosine 615, which is embedded in a
highly conserved region of the kinase domain of PERK, is essential
for autocatalytic activity. That is, mutation of Tyr-615 to
phenylalanine compromises the autophosphorylation capacity
of PERK and the phosphorylation of eIF2a in vitro and in vivo.
The Y615F mutation also impairs the ability of PERK to induce
translation of ATF4. Immunoblot analyses with a phosphospecific
antibody confirm the phosphorylation of PERK at Tyr-615
both in vitro and in vivo. Thus, our data classify PERK as a dual
specificity kinase whose regulation by tyrosine phosphorylation
contributes to its optimal activation in response to ER stress.