Protein / target
Dual specificity mitogen-activated protein kinase kinase 1
Protein at a glance
Biological role
Mitogen-activated protein kinase kinase kinase binding
Primary system
Nervous system
Strongest disease association
RASopathy
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
8 approved · 11 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis
Subcellular location
Domains and Gene Ontology detail (71)Hide
Domains & features
Gene Ontology
- Caxon
- Ccell cortex
- Ccentrosome
- Cciliary basal body
- Ccytosol
- Cdendrite cytoplasm
- Cearly endosome
- Cendoplasmic reticulum
- Cfocal adhesion
- Cglutamatergic synapse
- CGolgi apparatus
- Clate endosome
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Kinase signalling
- ·Dual specificity protein kinase which acts as an essential component of the MAP kinase s…
- ·MAP kinase kinase activity
- ·mitogen-activated protein kinase kinase kinase binding
- ·protein kinase activator activity
Transcriptional regulation
- ·Dual specificity protein kinase which acts as an essential component of the MAP kinase s…
- ·negative regulation of gene expression
- ·positive regulation of DNA-templated transcription
- ·positive regulation of gene expression
Synaptic signalling
- ·glutamatergic synapse
- ·postsynaptic density
- ·regulation of neurotransmitter receptor localization to postsynaptic specialization memb…
Muscle contraction
- ·positive regulation of muscle contraction
- ·regulation of vascular associated smooth muscle contraction
Excitatory neurotransmission
- ·glutamatergic synapse
Nuclear receptor signalling
- ·Dual specificity protein kinase which acts as an essential component of the MAP kinase s…
View underlying pathways (15)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
Dual specificity mitogen-activated protein kinase kinase 1 inhibitor
Appears in clinical studies involving melanoma, neoplasm, metastatic melanoma, metastatic colorectal cancer
Dual specificity mitogen-activated protein kinase kinase; MEK1/2 inhibitor
Appears in clinical studies involving metastatic melanoma, melanoma, glioma, neoplasm
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 1,320 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 19 total
neurofibromatosis type 1 · plexiform neurofibroma · neoplasm
hepatocellular carcinoma · colorectal cancer · malignant pancreatic neoplasm
lung cancer · melanoma · low grade glioma
colorectal cancer · acute myeloid leukemia · hematopoietic and lymphoid cell neoplasm
non-small cell lung carcinoma · malignant colon neoplasm · breast cancer
psoriasis vulgaris · acute myeloid leukemia · chronic myelomonocytic leukemia
Familial adenomatous polyposis · melanoma
melanoma · neoplasm · metastatic melanoma
melanoma · neoplasm · colorectal adenocarcinoma
Tractability
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Related literature
Papers indexed under “MAP Kinase Kinase 1” — a subject heading that covers this protein without being specific to it. Shown as context; not counted as this protein's own research activity.
Europe PMC literature, reached through a MeSH descriptor linked to this protein.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
This ranking differs from Open Targets' own: re-weighting moves genetically-evidenced diseases above more heavily co-mentioned ones. The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through 2 drugs that target this protein, so each event is news about that drug rather than about the protein directly.
- Trial status changed
Phase I Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib, or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification, or HER3/4 Mutation or KRAS Mutation
- New publicationMolecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.
- New publicationEfficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.
- Regulatory approval
Approval: Spexotras (EMA)
- New publicationCombination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced <i>BRAF</i>-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134.
- New publicationEncorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600E-Mutated Colorectal Cancer.
- Regulatory approval
Approval: Mektovi (EMA)
- New publicationEncorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial.
- Safety communication
Drug Safety Update: Trametinib (Mekinist▼): risk of gastrointestinal perforation and colitis
- New publicationImproved overall survival in melanoma with combined dabrafenib and trametinib.
- New publicationCombined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.
- Regulatory approval
Approval: Mekinist (EMA)
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.