MAP kinase

MAPK signaling begins when a ligand (e.g., EGF) binds a receptor tyrosine kinase (RTK), causing dimerization and autophosphorylation. This recruits adaptor proteins (GRB2, SOS) that activate RAS (a small GTPase) by promoting GDP-GTP exchange. Active RAS-GTP recruits and activates RAF (MAPKKK), which phosphorylates MEK (MAPKK), which in turn phosphorylates ERK (MAPK). Activated ERK translocates to the nucleus and phosphorylates transcription factors (e.g., c-Fos, c-Myc, Elk-1) that drive gene expression for cell cycle progression (G1/S transition) and proliferation.

Other MAPK subfamilies include p38 MAPK (activated by stress, inflammation, cytokines like TNF-α/IL-1) and JNK (c-Jun N-terminal kinase, involved in apoptosis and stress responses). These pathways are activated by heat, UV radiation, osmotic stress, and inflammatory signals.

Clinical significance: Mutations causing constitutive activation of this pathway are oncogenic. RAS mutations (KRAS, NRAS, HRAS) are found in ~30% of human cancers (pancreatic, colorectal, lung). BRAF V600E mutation is common in melanoma and hairy cell leukemia. Targeted therapies exploit this pathway: BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib) are used in BRAF-mutant melanoma. Cetuximab (anti-EGFR) is ineffective in KRAS-mutant colorectal cancer because the pathway is activated downstream of EGFR blockade.

The RAS-RAF-MEK-ERK pathway is also implicated in RASopathies (genetic syndromes with germline mutations in pathway components), including Noonan syndrome, Costello syndrome, and cardiofaciocutaneous syndrome, which feature developmental abnormalities, cardiac defects, and increased cancer risk.