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PKR-mediated signaling

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9833482

PubChem

R-HSA-9833482

Description

Interferon-induced, double-stranded RNA-activated protein kinase PKR (EIF2AK2) mainly halts cellular protein translation by phosphorylating eIF2α, which blocks the recycling of GDP-eIF2 to GTP-eIF2 required for cap-dependent translation initiation. PKR is constitutively expressed at low level, and its expression is up-regulated by interferon alpha/beta signaling. PKR is mainly localized in the cytoplasm with a small fraction in the nucleus (Tian & Mathews 2001).
PKR was identified in the 1970s (Friedman et al, 1972; Kerr et al., 1977). Its activation is characterized by the shifting of its monomer/dimer equilibrium towards the dimer, with subsequent autophosphorylation (reviewed by Sadler & Williams, 2007; Bou-Nader et al, 2019). Possible activating factors include binding of viral dsRNA to the PKR dsRNA binding domain (reviewed by Nallagatla et al, 2011), as well as cellular proteins (ISG15, PACT, DCP1A) and heparin (Patel & Sen, 1998; Dougherty et al., 2014; George et al., 1996; Fasciano et al., 2005; reviewed by Zhang et al, 2021). General translation shutdown by PKR can therefore be promoted by both viral infection and the integrated response of the cell to stress stimuli (reviewed by Pizzinga et al, 2019; Costa-Mattioli & Walter, 2020). Several cellular inhibitors of PKR activation and eIF2α phosphorylation by PKR have been identified and binding of PKR to viral proteins from RNA viruses (e.g. HIV, influenza A, RSV) has also been shown to contribute to inhibition (reviewed by Cesaro & Michiels, 2021). In addition to its role in translation shutdown via eIF2α, PKR affects translation through NFAR protein phosphorylation; it can also phosphorylate RNA helicase A, CDC2, and MKK6, thus modulating RNA metabolism, G2 arrest, and p38 MAPK activation. Finally, PKR can bind to TRAF proteins, the IkappaB kinase complex, GSK-3beta, and several inflammasome components leading to NF-kappa B activation, tau phosphorylation, apoptosis, and inflammasome activation (reviewed by Gil & Esteban, 2000; Garcia et al, 2007; Pindel & Sadler, 2011; Marchal et al, 2014; Yim & Williams, 2014; McKey et al, 2021).

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SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 45 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
A6NNZ2	Tubulin beta 8B	TUBB8B	view
O14920	Inhibitor of nuclear factor kappa-B kinase subunit beta	IKBKB IKKB	view
O15111	Inhibitor of nuclear factor kappa-B kinase subunit alpha	CHUK IKKA TCF16	view
O15287	Fanconi anemia group G protein	FANCG XRCC9	view
O75569	Interferon-inducible double-stranded RNA-dependent protein kinase activator A	HSD-14 HSD14 PACT PRKRA RAX	view
P04350	Tubulin beta-4A chain	TUBB4 TUBB4A TUBB5	view
P04637	Cellular tumor antigen p53	P53 TP53	view
P05198	Eukaryotic translation initiation factor 2 subunit 1	EIF2A EIF2S1	view
P06748	Nucleophosmin	NPM NPM1	view
P0DMV8	Heat shock 70 kDa protein 1A	HSP72 HSPA1 HSPA1A HSPA1B HSX70	view

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