MAPK14 in Context

MAPK14 (or p38 alpha or SAPK2a) is a proline-directed serine/threonine kinase activated by environmental stress or inflammatory signaling. While it is a well-conserved eukaryotic gene in the mitogen-activated protein kinase family, MAPK14 doesn’t typically respond to mitogens. All the same, MAPK14 is critically involved in cardiac development, sex determination, innate and adaptive immunity, and cellular homeostasis in neural, muscular, skeletal, adipose, and hepatic tissues.

There are more than 100 proteins that are directly phosphorylated (activated) by MAPK14, both in the nucleus and cytoplasm, influencing transcription, chromatin remodeling, cell cycle control, DNA repair, mRNA translation, protein degradation, autophagy, endocytosis, cytoskeletal elements, and metabolism. Depending on cell type and state of health, these influences are proving to be immensely complex and even seemingly contradictory.¹

MAPK14:  The Medium Is the Message

Canonically, MAPK14 is activated by a MAP2K-based phosphorylation cascade, typically induced by cytokine or G protein-coupled receptor docking or stressors (ROS, mechanical, or cellular damage). Non-canonically, MAPK14 can be activated via ZAP70 phosphorylation (induced by T cell receptor signaling) or binding to transforming growth factor beta activated protein 1. Given the great variety of provocations that induce MAPK14 activation and its downstream effects, dephosphorylation by various actors and negative feedback loops primarily serve to regulate its activity.²

A recently discovered pathway to MAPK14 activation involves signaling by toll-like receptor 4 (TLR4) in response to lipopolysaccharide stimulation. Lipopolysaccharide (LPS) is present on the surface of gram-negative bacteria and some viral proteins. Mice lacking functional MAPK14 in their astrocytes exhibit a diminished astroglial response to administered LPS. However, under these circumstances, microglia and neutrophil infiltration become more intense.³  Accordingly, challenging microglia with LPS stimulates TRL4 receptors and activates MAPK14. The microglial brake on inflammation and enabler of autophagy, ULK1, is then phosphorylated (inhibited) by MAPK14, initiating an innate inflammatory response.⁴  Infection by Covid-19 also acts via the TRL4/MAPK14 axis to trigger endotheliitis. To a considerable degree, the intensity of this response dictates the acute vascular severity of the infection and risk to a given patient’s life.⁵

MAPK14 Therapeutics:  Where do we go now?

While brief and appropriate responses help to repel invading organisms, prolonged engagement, outsized MAPK14 expression, or constitutive signaling can result in chronic inflammatory diseases, such as rheumatoid arthritis and chronic obstructive pulmonary disease. On the other hand, MAPK14 also exhibits cell type specific anti-inflammatory functions that attenuate particular tissue-damaging inflammatory responses. It is precisely this dual role of MAPK14 in the inflammatory response that complicates the use of systemic inhibitors to regulate chronic inflammation.⁶

So far, direct MAPK14 inhibitors have failed to achieve their goals in the clinic. Perhaps, inhibitors targeting specific downstream elements of MAPK14 signaling in particular tissues of interest are a way to increase effectiveness against a given pathology. Restricting the nuclear translocation of MAPK14 or finding ways to hasten its degradation in specific situations might also be promising. While it seems more likely that acute, punctuated MAPK14 inhibitors could get traction against certain cancers, chronic use of even slightly off target inhibitors against chronic inflammatory diseases causes collateral issues that will need to be addressed.¹

References

1. Canovas, B. and Nebreda, A. (2021) Diversity and Versatility of p38 Kinase Signalling in Health and Disease. Nature Reviews Molecular Cell Biology, 22, 346-366. https://www.nature.com/articles/s41580-020-00322-w
2. Han, J. et al. (2020) An Overview of Mammalian p38 Mitogen-Activated Protein Kinases, Central Regulators of Cell Stress and Receptor Signaling. F1000Res. 9, 653, Review. https://f1000research.com/articles/9-653/v1
3. Lo, U. et al. (2014) p38 alpha (MAPK14) Critically Regulates the Immunological Response and the Production of Specific Cytokines and Chemokines in Astrocytes. Nature Scientific Reports, 4, Article Number: 7405. https://www.nature.com/articles/srep07405
4. She, H. et al. (2018) Release the Autophage Brake on Inflammation: The MAPK14/p38 alpha-ULK1 Pedal. Autophagy, 14(6), 1097-1098. https://doi.org/10.1080/15548627.2018.1446626
5. Ma, Z. et al. (2022) A Human Pluripotent Stem Cell-Based Model of SARS-CoV-2 Infection Reveals an ACE2-Independent Inflammatory Activation of Vesicular Endothelial Cells Through TRL4. Stem Cell Reports, 17, 1-18. https://doi.org/10.1016/j.stemcr.2022.01.015
6. Arthur, J.S.C. and Ley, S.C. (2013) Mitogen-Activated Kinases in Innate Immunity. Nature Reviews Immunology, 13, 679-692. https://www.nature.com/articles/nri3495