Mitogen-activated protein kinase signaling pathways (MAPK pathways)

The JNK, ERK, and p38 MAPK pathways represent the three major branches of the mitogen-activated protein kinase (MAPK) signaling network, which serves as a central mechanism for eukaryotic cell regulation (Kyriakis & Avruch, 2012, Physiological Reviews). These pathways operate through a conserved three-tier kinase cascade—comprising a MAP kinase kinase kinase (MAPKKK), a MAP kinase kinase (MAPKK), and the MAP kinase (MAPK) itself—to relay extracellular signals to the nucleus (Zhang & Dong, 2007, Cellular & Molecular Immunology). The ERK pathway is predominantly activated by mitogens and growth factors, playing a critical role in cell proliferation, survival, and differentiation, and is frequently hyperactivated in human cancers (Pearson et al., 2001, Endocrine Reviews). In contrast, the JNK and p38 pathways are primarily activated by environmental stresses and pro-inflammatory cytokines, regulating apoptosis, inflammation, and the stress response (StatPearls, MAPK Signaling). Because of their pervasive role in disease, these pathways are major targets for drug development, with several MEK and BRAF inhibitors currently approved for oncology (PubChem). However, therapeutic targeting of these pathways is complicated by extensive crosstalk and feedback loops, which often lead to drug resistance and significant systemic toxicities, such as dermatologic and cardiac adverse events (PubMed, PMC4389125).

Other names

MAPK signaling cascadeMitogen-activated protein kinase pathwaysJNK/ERK/p38 cascadesStress-activated protein kinase pathwaysc-Jun N-terminal kinase pathwayExtracellular signal-regulated kinase pathwayp38 mitogen-activated protein kinase pathway

Inhibition of specific kinase components (e.g., RAF, MEK, or the MAPKs themselves) within the cascades to prevent phosphorylation of downstream substrates and halt pathological signaling (Kyriakis & Avruch, 2012).