MAPK/ERK signaling pathway
(Both “MAPK Signaling” and “MAPK/ERK Signaling” nav labels resolve here.)
The canonical ERK module follows RTK–Ras–Raf–MEK–ERK: growth factors induce receptor dimers, SOS-class GEFs load Ras·GTP, Raf (MAP3K) is recruited and activated, MEK1/2 (MAP2K) phosphorylates ERK1/2 on the TEY activation loop, and ERK drives immediate-early genes, cell-cycle entry, metabolic enzymes, and motility programs—with extensive crosstalk to PI3K/Akt, mTOR, and JNK/p38.
1. Key targets
Core kinase tiers
- Ras · Raf (MAP3K)
HRAS/NRAS/KRAS with ARAF/BRAF/CRAF (RAF1); dimerization, 14-3-3 release, and Ser259 de-repression are common control nodes.
- MEK1 / MEK2
MAP2K1/2 dual-specificity kinases—a pharmacologic bottleneck tuning ERK amplitude and localization.
- ERK1 / ERK2
MAPK3/MAPK1; nuclear shuttling and scaffolds (e.g., KSR) shape substrate portfolios and signal duration.
Upstream inputs
- RTK：EGFR、ERBB2、MET、FGFR、Trk…
- GPCR–Ras bridges, Ca²⁺/PKC regulation of Raf (context-dependent)
Downstream & feedback
- Elk-1、Fos、Jun；RSK、MNK → mRNA 翻译调控
- DUSPs, Sprouty, p-Raf1 Ser259 re-phosphorylation—feedback and desensitization
2. Suggested experimental readouts
MEK inhibitors can induce phospho-MEK feedback bands—pair p-ERK with total ERK, time courses, and fractionation.
- p-ERK1/2 (Thr202/Tyr204 vs Thr185/Tyr187—isoform/clone dependent)
- p-MEK1/2 (Ser217/221); p-CRAF (Ser338, etc.)
- c-Fos, EGR1 immediate-early genes (qPCR or IF)
- Cyclin D1, p-Rb (Ser807/811)—G1 progression
- Pair with p-AKT (Ser473) and p-S6 to separate MAPK vs PI3K branches
3. MAPK family: ERK vs p38 vs JNK
| Branch | MAPK | Upstream MAP2K (examples) | Typical stimuli |
|---|---|---|---|
| ERK1/2 | MAPK1 / MAPK3 | MEK1 / MEK2 | Growth factors, mitogens, oncogenic Ras/Raf |
| p38 | MAPK14 等 | MKK3 / MKK6（及 MKK4 语境） | Cytokines, osmotic/UV/oxidative stress |
| JNK / SAPK | MAPK8–10 | MKK4 / MKK7 | Stress, death-receptor cues, cytoskeletal tension |
TxY motifs differ (ERK Thr-Glu-Tyr; p38 Thr-Gly-Tyr; JNK Thr-Pro-Tyr)—pick phospho-clones carefully.
4. Cancer, resistance & drug context
- BRAF V600E: MEK ± BRAF combos in melanoma; watch acquired NRAS/RTK upregulation and CRAF dependence.
- KRAS G12C / 其它 RAS: ERK readouts remain central pharmacodynamic markers in the RAS inhibitor era.
- Paradoxical MEK activation: BRAFi can hyperactivate MAPK in BRAF-WT contexts via Raf dimers—mind model systems and combinations.
MAPK/ERK–related antibodies (curated)
5. Product lines & on-site search
Primary & phospho antibodies
p-ERK1/2, p-MEK1/2, p-CRAF, p-Raf (Ser259, etc.), pan-Ras, EGFR/HER2, DUSP6, Elk-1, c-Fos—WB/IHC/IF/FC per datasheet.
Active proteins & pull-down tools
Recombinant MEK/ERK, Ras·GTP detection (RBD), kinase activity kits—availability-dependent.
6. Inhibitors & tool compounds (summary)
Clinical agents are prescription drugs; for research, follow datasheets, ethics, and multi-kinase off-target notes.
MEK1/2; standard with BRAFi in melanoma.
MEK1/2; BRAFi partner regimens (label-dependent).
MEK1/2; NF1 plexiform neurofibroma contexts.
V600-selective BRAF inhibitors (isoform profiles differ).
ERK1/2 inhibitor; feedback/resistance studies.
MEK tool compounds—mind solubility/permeability.
Multi-kinase (Raf/VEGFR, etc.)—interpret with target panels.
7. Pathway schematic
- RTK → Grb2–SOS → Ras·GTP
- Raf dimers activate MEK
- MEK dual-phosphorylates ERK TEY loop
- ERK nuclear programs: IEGs & cell-cycle
8. Pathway biology overview
ERK couples nutrient and mitogenic cues: it sets proliferation/differentiation boundaries in development and homeostasis, and in cancer is amplified by Ras/Raf/RTK lesions yet often persists via feedback and bypass—clinically druggable yet hard to eradicate alone. Cooperation with PI3K–mTOR couples growth to biosynthesis and glycolytic gene expression—a classic metabolic–growth intersection.
- Senescence/stress: links to p53/p21 and ERK pulse frequency biology
- Synaptic plasticity: ERK–transcription coupling (model-dependent)
9. Related pathways on this site
10. External databases & modification resources
- KEGG: hsa04010 MAPK signaling pathway
- Reactome: MAPK family signaling cascades
- WikiPathways (search: MAPK ERK)
- PhosphoSitePlus (ERK/MEK/Raf modification sites)
11. References
Cascade & regulation
- • Pearson G, et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 22(2):153-83.
- • Roskoski R Jr. (2012). ERK1/2 MAP kinases: structure, function, and regulation. Biochem Biophys Res Commun. 422(1):1-5.
Cancer & targeting
- • Dhillon AS, et al. (2007). MAP kinase signalling pathways in cancer. Oncogene. 26(22):3279-90.
- • Prahallad A, et al. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 483(7387):100-3.