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).
Organ Systems
immune-hematologic
nervous
cardiovascular
digestive
reproductive
Pathway Steps
RTK ligand (EGF, FGF, PDGF, etc.) → receptor dimerization + autophosphorylation — via pY motifs recruit GRB2 → SOS guanine nucleotide exchange factor. Ligand-induced receptor dimerization creates phosphotyrosine docking sites that recruit GRB2-SOS, converting an extracellular growth signal into RAS activation. EGFR/HER2 amplification or activating mutations feed this step — the basis of anti-EGFR/HER2 therapy.
RAS-GDP → RAS-GTP — via SOS GEF activity; opposed by RAS-GAP; intrinsic GTPase mutations (G12, G13, Q61) lock in GTP state. SOS (a GEF) loads RAS with GTP; RAS-GAPs such as NF1 switch it off. Oncogenic mutations at G12/G13/Q61 cripple the GTPase, locking RAS on — KRAS is the most frequently mutated oncogene in human cancer, long “undruggable” until the recent KRAS-G12C covalent inhibitors (sotorasib).
RAS-GTP → RAF dimerization + activation — via A-RAF / B-RAF / C-RAF; BRAF-V600E mutation drives monomeric constitutive activity. Active RAS drives RAF (A/B/C-RAF) dimerization. BRAF-V600E activates RAF as a monomer (bypassing RAS), driving melanoma and thyroid cancer; paradoxically, first-generation RAF inhibitors can transactivate RAF dimers in RAS-mutant cells — the basis of paradoxical MAPK activation.
RAF active → MEK1/2 dual phosphorylation — via MEK is a dual-specificity Tyr/Thr kinase — narrow substrate (ERK1/2 only). RAF phosphorylates MEK1/2, dual-specificity kinases with an unusually narrow substrate range (essentially only ERK1/2). That bottleneck makes MEK a clean drug target — MEK inhibitors (trametinib) are paired with BRAF inhibitors to delay resistance in melanoma.
MEK1/2 active → ERK1/2 TEY motif phosphorylation — via ERK1/2 have ~200 substrates — broad cytoplasmic + nuclear. MEK dual-phosphorylates the ERK1/2 TEY motif. ERK is the cascade’s effector hub with ~200 substrates spanning cytoplasm and nucleus — the convergence point that amplifies and diversifies the signal, which is why ERK-pathway output is so pleiotropic.
ERK1/2 active → Elk-1 / c-Fos / c-Myc / RSK / MNK phosphorylation — via → cyclin D1, proliferation; cap-dependent translation via eIF4E. Nuclear ERK drives immediate-early transcription (Elk-1→c-Fos, c-Myc) toward cyclin D1 and proliferation, while the RSK/MNK branches boost cap-dependent translation (eIF4E). This proliferative gene program is the oncogenic payload of constitutive RAS-RAF-MEK-ERK signaling.
ERK1/2 active → negative feedback on RAF / MEK / SOS — via transient activation kinetics; sustained signaling overrides feedback. ERK phosphorylates upstream RAF, MEK, and SOS to dampen the cascade, normally giving transient, pulsatile activation. Oncogenic mutations override this feedback for sustained signaling — and relieving the feedback is itself a mechanism of adaptive resistance to RAF/MEK inhibitors.