ERK1/2 in immune signalling

Abstract

Extracellular signal-related kinases 1 and 2 (ERK1/2) are the final components of the mitogen-activated protein kinase (MAPK) phosphorylation cascade, an integral module in a diverse array of signalling pathways for shaping cell behaviour and fate. More recently, studies have shown that ERK1/2 plays an essential role downstream of immune receptors to elicit inflammatory gene expression in response to infection and cell or tissue damage. Much of this work has studied ERK1/2 activation in Toll-like receptor (TLR) pathways, providing mechanistic insights into its recruitment, compartmentalisation and activation in cells of the innate immune system. In this review, we summarise the typical activation of ERK1/2 in growth factor receptor pathways before discussing its known roles in immune cell signalling with a focus downstream of TLRs. We examine emerging research uncovering evidence of dysfunctional ERK1/2 signalling in inflammatory diseases and discuss the potential therapeutic benefit of targeting ERK1/2 pathways in inflammation.

Keywords: Toll-like receptors; cytokines; extracellular signal-regulated kinases; inflammation; innate immunity; receptor signalling.

Figure 1.. Core RAS–ERK pathway downstream of RTKs.

Following ligand binding, activated RTKs recruit Grb2 via its SH2 domain. Grb2 associates with the GEF SOS which allows activation of GTP-bound RAS GTPase at the plasma membrane. As part of the core RAS–ERK pathway, RAS activation of RAF then promotes phosphorylation of MEK which phosphorylates and activates ERK. In a negative feedback loop, active ERK phosphorylates SOS to inhibit its interaction with Grb2 and prevent further RAS activation. Cytoplasmic substrates of activated ERK include RSK, MSK and MNK kinase pathways, and nuclear ERK import allows activation of its many nuclear substrates including transcription factors for gene expression in multiple cell fate pathways.

Figure 2.. ERK activation downstream of TLR4.

(A) LPS binding to TLR4 on the cell surface stimulates the recruitment of MYD88 through a homologous TIR domain interaction (shown in purple). Subsequent MYD88-IRAK oligomer formation activates TRAF6 and TAK1 to promote IKK-mediated degradation of IκB to allow the nuclear translocation of NF-κB for inflammatory cytokine expression. IKK also promotes proteolysis of TPL2 inhibitory protein p105 to activate the TPL2-ERK pathway for ERK phosphorylation and activation of nuclear AP-1 component c-Fos. (B) LPS-activated TLR4 directly interacts with transmembrane adaptor SCIMP through a TIR-non-TIR interaction. SCIMP scaffolds Lyn kinase through its proline-rich domain (PRD; shown in green) and recruits a subset of ERK to TLR4 on the cell surface and macropinosomes for phosphorylation of c-Fos which translocates to the nucleus for pro-inflammatory cytokine expression. Dashed blue arrow between pathways shows possible TPL2 activation of SCIMP-scaffolded ERK.