Category: signaling
The RAS-RAF-MEK-ERK MAP kinase cascade is the canonical RTK → mitogen signaling pathway: RTK ligand binding (EGF, FGF, PDGF, etc.) → receptor dimerization + autophosphorylation → SOS recruitment via GRB2 → RAS-GDP → RAS-GTP (small GTPase, 3 isoforms: H-, K-, N-RAS). RAS-GTP recruits RAF (A-RAF, B-RAF, C-RAF) → dimerization + autophosphorylation → RAF active. RAF phosphorylates MEK1/2 → MEK1/2 phosphorylates ERK1/2 → activated ERK has 200+ substrates: cytoplasmic (RSK → S6 ribosomal protein), nuclear (Elk-1, c-Fos, c-Myc, MNK → eIF4E → cap-dependent translation), regulatory (negative feedback on RAF/MEK). Outcomes: proliferation (G1→S via cyclin D1), differentiation (lineage-specific), survival (anti-apoptotic in some contexts). Cancer driver: ~30% of all human cancers have RAS mutations (KRAS-G12C, G12D in NSCLC/PDAC/CRC; NRAS in melanoma); ~50% of melanomas have BRAF-V600E. Therapeutic pipeline: RAF inhibitors (vemurafenib, dabrafenib, encorafenib — BRAF-V600E selective); MEK inhibitors (trametinib, cobimetinib, binimetinib); ERK1/2 inhibitors (ulixertinib — investigational); RAS-G12C (sotorasib, adagrasib — first direct RAS inhibitors). Combinations (BRAF+MEK) overcome paradoxical activation in WT cells. Cross-talk: PI3K-AKT (parallel cascade, often co-targeted), Wnt, JAK-STAT. Cross-links: [[tyrosine_kinase_inhibition]] (upstream RTKs), [[cell_cycle_cdk]] (downstream cyclin D1), [[pi3k_akt_signaling]] (parallel).