MAPK

Mitogen-activated protein kinases (MAPKs) are a family of conserved serine/threonine/tyrosine protein kinases that transduce extracellular signals into cellular responses. They operate in three-kinase cascades in which a MAPK kinase kinase (MAPKKK) activates a MAPK kinase (MAPKK), which in turn activates a MAPK by phosphorylation on a threonine- and tyrosine-containing activation loop. MAPKs regulate processes such as proliferation, differentiation, stress responses, and apoptosis.

MAPK subfamilies include ERK1/2 (encoded by MAPK3/MAPK1), JNKs (MAPK8-10), p38 MAPKs (MAPK14-APK6), and ERK5 (MAPK7, also called BMK1). ERK1/2 are primarily activated by growth factors and mitogens via the Ras-Raf-MEK-ERK axis and promote cell cycle progression. JNK and p38 respond to inflammatory cytokines and environmental stress; ERK5 responds to growth and mechanical signals.

Activation involves sequential phosphorylation: ERK1/2 by MEK1/2; JNKs by MKK4/7; p38 by MKK3/6; ERK5 by MEK5. Once activated, MAPKs can translocate to the nucleus where they phosphorylate transcription factors such as ELK1, AP-1 components (c-Fos, c-Jun), and CREB, leading to gene expression changes; MAPKs also phosphorylate cytosolic substrates affecting mRNA translation, cytoskeletal dynamics, and metabolism (e.g., RSK, MNK).

Regulation is achieved through phosphatases such as DUSPs/MKPs that dephosphorylate MAPKs; scaffold proteins like KSR organize signaling complexes; signaling is tightly controlled by feedback and cross-talk with other pathways.

Dysregulation of MAPK signaling is linked to cancer, inflammatory, and neurodegenerative diseases. Therapeutic strategies include MEK inhibitors for ERK pathway–driven cancers (e.g., trametinib, cobimetinib); p38 and JNK inhibitors are under investigation, with resistance and toxicity presenting challenges.

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