Eukaryotic translation initiation factor 2-alpha kinase 2 (PKR)-p38 mitogen-activated protein kinase (p38 MAPK) axis (PKR-p38 MAPK axis)

The Eukaryotic translation initiation factor 2-alpha kinase 2 (PKR)-p38 mitogen-activated protein kinase (MAPK) axis is a signaling pathway that plays a central role in the cellular response to viral infection, oxidative stress, and inflammatory stimuli [UniProt P19544, Q16539]. PKR is a double-stranded RNA-activated kinase that, upon sensing stress, undergoes autophosphorylation and subsequently activates the p38 MAPK pathway, often through intermediate MAP kinase kinases like MKK3 and MKK6 [PubMed: 21854987]. This axis is a major regulator of the innate immune response, driving the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [PubMed: 15661923]. In neurodegenerative diseases, particularly Alzheimer's disease, the PKR-p38 MAPK axis is associated with tau protein hyperphosphorylation and neuronal apoptosis, making it a significant area of therapeutic interest [PubMed: 28285059]. In oncology, the axis can exhibit dual roles, either promoting tumor suppression through stress-induced cell death or facilitating cancer cell survival under metabolic stress [PubMed: 25639554]. Pharmacological modulation of this axis typically involves small-molecule inhibitors targeting either the ATP-binding site of PKR or the catalytic activity of p38 MAPK [PubChem]. While targeting this pathway offers potential for treating chronic inflammatory and neurodegenerative conditions, challenges include maintaining specificity to avoid systemic toxicity and managing the potential for immunosuppression [PubMed: 16497886].

Other names

PKR-p38 signaling pathwayEIF2AK2-MAPK14 axisDouble-stranded RNA-activated protein kinase-p38 MAPK pathwayPKR-p38 MAPK signaling cascade

The mechanism of action involves the competitive or non-competitive inhibition of the ATP-binding sites of PKR or p38 MAPK, thereby blocking the phosphorylation of downstream substrates such as eIF2α and various transcription factors, which ultimately suppresses inflammatory cytokine production and stress-induced apoptosis.