MAPKpathways

MAPK pathways, or mitogen-activated protein kinase pathways, are evolutionarily conserved signaling cascades that transduce extracellular signals into a broad range of cellular responses. The best characterized branches are ERK1/2, JNK, and p38. Each pathway follows a three-tier cascade in which a MAP kinase kinase kinase (MAPKKK) activates a MAP kinase kinase (MAPKK), which then activates a MAP kinase (MAPK). Examples: the RAF–MEK–ERK cascade; the TAK1/ASK1–MKK4/7–JNK cascade; and the TAK1/MKK3/6–p38 cascades. Activated MAPKs phosphorylate diverse substrates, including transcription factors such as ELK1 and AP-1, cytoskeletal regulators, and metabolic enzymes, to elicit context-dependent outcomes.

Activation stimuli include growth factors and mitogens that engage receptor tyrosine kinases, as well as stress signals, cytokines, and GPCR ligands. Scaffold proteins and subcellular localization contribute to signaling specificity, while feedback loops shape duration and amplitude. Termination is achieved by dual-specificity phosphatases (DUSPs or MKPs) that dephosphorylate MAPKs, and by phosphatases targeting upstream components.

Functions of MAPK pathways include regulation of cell proliferation, differentiation, survival, apoptosis, metabolism, and synaptic plasticity. They influence gene expression programs through transcription factors and chromatin modifiers, and can cross-talk with other signaling networks such as PI3K–AKT and NF-κB.

Clinical relevance: dysregulation of MAPK signaling is linked to cancer and inflammatory or neurodegenerative diseases. The pathways are targets of therapeutic intervention; MEK inhibitors (for example trametinib) have been approved for certain cancers, while ERK inhibitors are in development. JNK and p38 inhibitors have shown limited utility due to roles in normal physiology and side effects. In research, MAPK pathways serve as models for understanding signal integration and pathway crosstalk.