MEK1

Official Full Name

mitogen-activated protein kinase kinase 1

Organism

Homo sapiens

GeneID

5604

Background

The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

Synonyms

MEL; CFC3; MEK1; MKK1; MAPKK1; PRKMK1;

Bio Chemical Class

Kinase

Protein Sequence

MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKVGELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSYGMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV

Open

Disease

Cardiac arrest, Lung cancer, Melanoma, Solid tumour/cancer, Thyroid cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

1 +

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Detailed Information

The MAP2K1 gene, located on chromosome 15q22.31, encodes the Mitogen-Activated Protein Kinase 1, commonly referred to as MEK1. This gene belongs to the dual-specificity protein kinase family and functions specifically within the MAP kinase signaling module. MEK1 is a serine/threonine and tyrosine kinase, characterized by its unique ability to phosphorylate both threonine and tyrosine residues within its substrate MAP kinases, specifically ERK1 (MAPK3) and ERK2 (MAPK1), on the conserved Thr-Glu-Tyr (TEY) motif located in their activation loop. Structurally, MEK1 contains a canonical kinase domain but lacks regulatory Src homology 2 (SH2) or 3 (SH3) domains, instead possessing distinct docking sites for upstream activators (like RAF kinases) and downstream substrates (ERK1/2), along with a nuclear export signal (NES) and a proline-rich region near its N-terminus. The N-terminal region contains crucial negative regulatory elements, including sites for inhibitory phosphorylation. MAP2K1 is highly conserved across evolution, highlighting its fundamental role in cellular signaling. Its paralog, MAP2K2 (MEK2), shares significant sequence homology (approximately 80% in the kinase domain) and functional redundancy, allowing for compensatory mechanisms in some contexts. However, specific non-redundant functions for each isoform are increasingly recognized. Gene Ontology annotations precisely reflect its role as a transferase with protein tyrosine kinase activity and its involvement in critical signaling cascades like the Toll-Like Receptor 7/8 pathway and Prolactin Signaling.

Biological Significance and Functional Mechanisms

MEK1 occupies a critical and non-redundant position as the direct upstream activator of ERK1/2 within the canonical RAS-RAF-MEK-ERK signaling cascade, often referred to as the MAPK/ERK pathway. This pathway serves as a major conduit for transmitting extracellular signals initiated by growth factors, cytokines, hormones, and mitogens binding to their cognate receptors into the nucleus to elicit profound changes in gene expression, cell behavior, and fate. Upon receptor activation, GTP-bound RAS recruits and activates RAF kinases (ARAF, BRAF, CRAF) to the plasma membrane. Activated RAF kinases then phosphorylate MEK1 on two serine residues within its activation loop (S218 and S222 in MEK1). This dual phosphorylation relieves autoinhibition and fully activates MEK1. Activated MEK1 subsequently phosphorylates its exclusive substrates, ERK1 and ERK2, on both a threonine and a tyrosine residue within their TEY activation loop motif, thereby activating them. Activated ERKs then phosphorylate a vast array of cytoplasmic and nuclear substrates, including transcription factors, kinases, cytoskeletal proteins, and regulators of apoptosis, collectively orchestrating diverse cellular responses such as proliferation, differentiation, survival, adhesion, migration, metabolism, and specific immune functions.

Figure 1. Schematic diagram illustrating MEK1-dependent and independent ERK1/2 activation. (Bauerfeld C, et al., 2017)

MEK1 also plays a role in regulating the spatiotemporal dynamics of ERK signaling through scaffolding proteins and subcellular localization. Recent research reveals its involvement in unexpected contexts, such as activating BRAF in a kinase suppressor of ras (KSR1/2)-dependent manner by promoting KSR-BRAF dimerization, and regulating organelle dynamics like Golgi fragmentation during mitosis and endosomal recycling. It also modulates the activity and localization of nuclear receptors like PPARγ, influencing differentiation and metabolic programs. The pathway is subject to intricate negative feedback regulation, including ERK-mediated phosphorylation of upstream components like SOS, RAF, and MEK itself, ensuring signal attenuation and homeostasis.

Clinical Relevance and Therapeutic Targeting

The pivotal role of the MAPK/ERK pathway, and specifically MEK1, in regulating cell growth and survival makes it a frequent target of dysregulation in human diseases, most notably cancer and developmental disorders. Somatic gain-of-function mutations in MAP2K1 are well-documented oncogenic drivers across various malignancies. These mutations predominantly cluster in the N-terminal negative regulatory domain (e.g., deletions like ΔExon3, point mutations like P124L/S, F53L/S/V, Q56P, K57N) or within the catalytic kinase domain near the ATP-binding site, leading to constitutive kinase activation independent of upstream signals. Such MAP2K1 mutations are frequently observed in melanoma, histiocytic neoplasms (e.g., Langerhans cell histiocytosis, Erdheim-Chester disease), ovarian cancer, lung adenocarcinoma (particularly KRAS-mutant), and less commonly in colorectal, pancreatic, and other cancers. These mutations often co-occur with other pathway alterations (e.g., BRAF V600E, RAS mutations, NF1 loss) but can also act as sole drivers.

Furthermore, germline mutations in MAP2K1 cause Cardiofaciocutaneous Syndrome 3 (CFC3), a rare developmental disorder belonging to the RASopathies spectrum, characterized by distinctive craniofacial features, cardiac defects, skin abnormalities, and intellectual disability, resulting from hyperactive ERK signaling during embryogenesis. Isolated melorheostosis, a sclerosing bone dysplasia, has also been linked to specific mosaic MAP2K1 mutations. The clinical imperative to target this pathway led to the development of highly specific ATP-non-competitive allosteric MEK1/2 inhibitors (MEKis), such as trametinib, cobimetinib, binimetinib, and selumetinib. These drugs bind to a pocket adjacent to the ATP-binding site, locking MEK1/2 in an inactive conformation. MEKis have demonstrated significant clinical benefit, particularly in BRAF V600E/K-mutant melanoma, BRAF V600E-mutant non-small cell lung cancer, and histiocytic neoplasms harboring MAP2K1 or other pathway mutations. Selumetinib is FDA-approved for neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas, where it targets hyperactive RAS signaling. Resistance to MEK inhibition remains a challenge, often arising through mechanisms like acquired mutations in MEK1 itself, reactivation of ERK signaling via alternative pathways, or bypass mechanisms involving other kinases. Consequently, combination therapies are actively being explored. The clinical success of MEK inhibitors validates MEK1 as a critical therapeutic target and exemplifies the translation of fundamental kinase biology into impactful precision oncology and rare disease treatments.

References:

Bauerfeld C, Samavati L. Role of MEK1 in TLR4 Mediated Signaling. J Cell Signal (Los Angel). 2017 Mar;2(1):135.
Hedayat M, Jafari R, Majidi Zolbanin N. Selumetinib: a selective MEK1 inhibitor for solid tumor treatment. Clin Exp Med. 2023 Jun;23(2):229-244.

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