MAPK1, An Elusive Regulator of Innate Immunity

Mitogen-Activated Protein Kinases (MAPKs) and MAPK Signaling Cascade

Mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases involved in converting extracellular signals to a large spectrum of fundamental cellular processes such as apoptosis, cell division, metabolism survival, etc. This signaling cascade is known as the MAPK pathway. MAPKs are highly conserved among eukaryotes, which mirrors its indispensable function in maintaining cellular physiology. A total of 14 MAPKs have been characterized in mammals, and these MAPKs can be categorized into two forms – conventional and atypical¹. Conventional MAPKs include Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun amino (N)-terminal kinases 1/2/3 (JNK1/2/3), p38 isoforms, and ERK5, while atypical MAPKs, which are less studied, include ERK3/4, ERK7, and Nemo-like kinase (NLK). All MAPKs contain the Ser/Thr kinase domain, which is needed to catalyze the phosphorylation of serine and threonine residues, therefore activating downstream effectors of the MAPK signaling pathway.

MAPK1 Acts in the ERK1/2 Signaling Module

MAPK1, commonly referred to as ERK2, is a conventional MAPK. Known as the ‘classical’ MAPK, ERK2 is involved with ERK1 (MAPK3) in the ERK1/2 signaling module. ERK1 and ERK2 are highly similar, sharing 83% amino acid identity¹. A plethora of upstream signals such as growth factors, inflammatory cytokines, cellular stress, and mitogens can activate ERK1/2. In turn, activated ERK1/2 phosphorylates and activates key transcription factors such as c-Myc, c-Fos, Elk1, and Ets, which serve to initiate the production of response proteins. At present, there are about 200 known substrates of ERK1/2², which partake in various cellular processes to respond to upstream signals appropriately.

Involvement of MAPK1 in Innate Immunity

Because the ERK1/2 signaling module was found to be a critical regulator of cell cycle and proliferation, its role in cancer has been extensively studied³. However, MAPK signaling is also discovered to play pivotal roles in regulating innate immunity. Innate immunity serves as the first line of defense in the presence of pathogenic infections where the pattern recognition receptors (PPRs) recognize pathogen-associated molecular patterns (PAMPs) and induce inflammatory responses such as the release of chemokines and cytokines via immune signaling pathways such as the MAPK pathway⁴.

One group of PPRs known as Toll-like receptors (TLRs) activates the MAPK signaling cascade in the presence of PAMPs to induce the production of cytokines such as Tumor necrosis factor-α (TNFa), interleukin-1 (IL-1), IL-6, and IL-12⁵. ERK is especially important in regulating TNFa production at a transcriptional and post-transcriptional level. A group of researchers showed that mice deficient in TPL2, a MAPK kinase that acts upstream of ERK1/2, cannot produce TNF-α in the presence of an inflammatory stimuli⁶. Therefore, MAPKs, including ERK, are critical for TNF-α post-transcriptional regulation. Transcriptionally, ERK is involved in inducing TNF-α gene expression by activating transcriptional factor AP-1 and/or activating protein kinases MSK1/2 which in turn activates CREB and transcription ATF-1, components important for TNF-α production⁷.

More insights have been shed in recent years, demystifying the role of MAPKs such as MAPK1 in innate immunity. However, current knowledge is still relatively limited. More studies would have to be done to further elucidate the relationship between ERK, TLRs, and cytokine production, especially in a cell-specific manner.

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References

1. Cargnello, M. & Roux, P. P. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases. Microbiol Mol Biol Rev 75, 50–83 (2011). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063353/
2. Wortzel, I. & Seger, R. The ERK Cascade. Genes Cancer 2, 195–209 (2011). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128630/
3. Guo, Y.-J. et al. ERK/MAPK signalling pathway and tumorigenesis (Review). Experimental and Therapeutic Medicine 19, 1997–2007 (2020). https://pubmed.ncbi.nlm.nih.gov/32104259/
4. Arthur, J. S. C. & Ley, S. C. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13, 679–692 (2013). https://www.nature.com/articles/nri3495
5. Dong, C., Davis, R. J. & Flavell, R. A. MAP kinases in the immune response. Annu Rev Immunol 20, 55–72 (2002). https://pubmed.ncbi.nlm.nih.gov/11861597/
6. Rousseau, S. et al. TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNFα in LPS-stimulated macrophages. Journal of Cell Science 121, 149–154 (2008). https://journals.biologists.com/jcs/article/121/2/149/35225/TPL2-mediated-activation-of-ERK1-and-ERK2
7. Sabio, G. & Davis, R. J. TNF and MAP kinase signaling pathways. Semin Immunol 26, 237–245 (2014). https://pubmed.ncbi.nlm.nih.gov/24647229/