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. Author manuscript; available in PMC: 2018 Mar 20.
Published in final edited form as: Curr Opin Chem Biol. 2013 May 4;17(3):346–352. doi: 10.1016/j.cbpa.2013.04.009

Figure 3.

Figure 3

Small molecule modulation of PERK signaling can be mediated by targeting eIF2α phosphatase complexes. PERK activation increases eIF2α phosphorylation, which in turn attenuates translation and increases expression of stress-responsive transcription factors. This pathway is negatively regulated by a phosphatase complex between protein phosphatase 1 and the constitutively expressed regulatory subunit CreP (PP1–CreP) and/or a stress-induced regulatory subunit GADD34 (PP1–GADD34). Small molecules that target these complexes can modulate eIF2α-dependent signaling, effectively mimicking PERK activation. Salubrinal inhibits both the PP1–CreP and PP1–GADD34 phosphatase complexes, allowing for increased eIF2α phosphorylation in the absence of stress. Guanabenz selectively targets PP1–GADD34, providing a mechanism to prolong PERK-dependent eIF2α phosphorylation signaling activation in response to ER stress. Figure adapted from Wiseman et al. [39].