MEK1

MEK1, also known as MAP2K1 and MKK1, 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. MEK1 is widely expressed, with extremely low levels in brain. It 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, MEK1 is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. Binding 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 and MEK2. MEK1 has been shown to export PPARG from the nucleus. The MAPK 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. MKK1 catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Defects in MEK1 can cause cardiofaciocutaneous syndrome.

MEK1 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>MEK1/MAP2K1/MKK1

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>MEK1/MAP2K1/MKK1

MEK1 Related Pathways

• TGF-beta Signaling
• EGFR Signaling Pathway
• Cytokine Receptor Signaling

MEK1 Alternative Names

MEK1, MAP2K1, MKK1, MAPKK1, PRKMK1 [Homo sapiens]

Mek1, Map2k1, MKK1, MAPKK1, MEKK1, Prkmk1 [Mus musculus]

Summaries for MEK1

Entrez Gene summary for MEK1:

The protein encoded by MAP2K1 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]

Wikipedia summary for MEK1:

Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MEK1 gene.

Human MEK1 Protein General Information

 

• Protein names: ERK activator kinase 1 MAPK/ERK kinase 1 , Short name=MEK 1
• Sequence length: 393 AA.
• Sequence similarities: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Contains 1 protein kinase domain.
• Post-translational modification: Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (RAF or MEKK1) positively regulates kinase activity. Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK. MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK. Ref.3 Ref.9 Ref.10 Ref.12 Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
• Subunit structure: Found in a complex with at least BRAF, HRAS1, MAP2K1, MAPK3/ERK1 and RGS14 By similarity. Forms an heterodimer with MAP2K2/MEK2 By similarity. Forms heterodimers with KSR2 which further dimerize to form tetramers By similarity. Interacts with ARBB2, LAMTOR3, MAPK1/ERK2, MORG1 and RAF1 By similarity. Interacts with PPARG and with isoform 1 of VRK2. Interacts with Yersinia yopJ. Interacts with SGK1.
• Subcellular location: Cytoplasm › cytoskeleton › centrosome. Cytoplasm › cytoskeleton › spindle pole body. Cytoplasm. Nucleus. Note: Localizes at centrosomes during prometaphase, midzone during anaphase and midbody during telophase/cytokinesis.
• Tissue specificity: Widely expressed, with extremely low levels in brain.
• Involvement in disease: Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Enzyme regulation: Ras proteins such as HRAS mediate the activation of RAF proteins such as RAF1 or BRAF which in turn activate extracellular signal-regulated kinases (ERK) through MAPK (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-back regulation by its substrate kinases, such as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating dephosphorylation of the activating residues Ser-218 and Ser-222. Inhibited by serine/threonine phosphatase 2A. Many inhibitors have been identified including pyrrole derivatives, TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766.
• Domain: The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.

General information above from UniProt

Function for MEK1 Protein

UniProtKB:

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. 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.

Genatlas:

• MEK1 is implicated in regulation of a parallel but distinct cascade that leads to phosphorylation of N-terminal sites on c-Jun
• MEK1 stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals
• MEK1 activates the MAP kinase ERK1 (PRKM3)
• MEK1 plays an essential role in extra-embryonic ectoderm during placentogenesis
• MEK1 is the dual-specificity kinase that mediate ERK1 and ERK2 activation during adhesion and growth factor signaling
• MEK1 mediates the regulation of MAP2K2 in the context of a previously undiscovered MAP2K1 / MAP2K2 complex 
• MEK1 is a crucial modulator of Mek and Erk signaling and MEK1 have potential implications for the role of MAP2K1 and MAP2K2 in tumorigenesis
• MEK1 may contribute to the stability of the NEK10/RAF1 interaction

Homology for human MEK1

• homolog to murine Map2k1
• homolog to C.elegans Y54e10bl.6

Phenotype Information for MEK1

• Gene/Locus: MAP2K1, PRKMK1, MKK1, MEK1
• Phenotype: Cardiofaciocutaneous syndrome

Phenotype Information for MEK1 from OMIM (Online Mendelian Inheritance in Man)