Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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mitogen-activated protein kinase kinase 2(MAP2K2) mitogen-activated protein kinase kinase 2(MAP2K2) Related Genes Homo sapiens
CYTOBAND 19p13.3, 7q32.3,
GENERIF_SUMMARY MEK2 interacts with ERK1. This interaction is mediated via a conserved N-terminal docking site in MEK2., MEK2 interacts with ERK2. This interaction is mediated via a conserved N-terminal docking site in MEK2. Note that this interaction was demonstrated using rat ERK2., MEK2 activity ad dual-phosphorylation were undetectable in expanding and self-renewing hematopoietic progenitors (HP). Adding IL-3, inducing maturation and cell death in HP, led to sustained high levels of MEK2 activity and dual-phosphorylation., Activation of a Src-dependent Raf-MEK1/2-ERK signaling pathway is required for IL-1alpha-induced upregulation of beta-defensin 2 in human middle ear epithelial cells., MEK2 and p38 in IFN-gamma-mediated signal transduction and induction of C/EBP beta expression and activity associated with interleukin-6 (IL-6) secretion in colon epithelial cells., Data show that p-MEK1/2 and p-ERK1/2 are present in neurons in the initial stages of neurofibrillary degeneration in Alzheimer's disease, before deposition of beta-amyloid., MK2 phosphorylates TSC2, which creates a 14-3-3 binding site and thus regulates the cellular function of the TSC2 tumor suppressor protein, Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I-induced increase in VEGF secretion and promoter activity, results show that p38-mediated dephosphorylation of MEK1,2 mediates initiation of apoptosis, MAPK activated protein kinase-2 mediates both ERK- and p38 MAPK-dependent neutrophil responses., HuR and MK2 in regulating the expression of uPA and uPAR genes at the posttranscriptional level, MEK1,2 response element that mediates angiotensin II-stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation., Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38mapk and MEK1/2 similarly increase cytolysis resulting from O2-., Results suggest a physiological link between beta-dystroglycan and mitogen-activated protein kinase kinase 2 (MEK2), and localize MEK with dystroglycan in membrane ruffles., Has distinct ways to contribute to a regulated ERK activity and cell cycle progression., Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress., X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively, The ability of constitutively-active human MEK2 to stimulate ERK phosphorylation and to induce the neoplastic transformation of NIH 3T3 cells required the integrity of the D-site was found., PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1, a novel signaling pathway involving MKK-2 and ERK1/2 may down-regulate the activity of PABP and eIF4E by controlling their phosphorylation and compensates for the effect of excess cellular PABP, findings demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase pathway, BRAF, MEK1 and MEK2 cause cardio-facio-cutaneous syndrome, These data suggest a role for mitochondrially generated reactive oxygen species and Ca(2+) in the redox cell signaling path-ways, leading to ERK activation and adaptation of the pathological stress mediated by oxidized lipids such as lysoPC., Taxotere and MEK1/2 inhibitors have the potential to suppress mammary tumor growth in vivo., Inhibition of overactive ras-MEK-ERK pathway in HepG2 cells can correct the defect in VLDL assembly leading to the secretion of VLDL-sized particles, similar to primary hepatocytes, implicating the MEK-ERK cascade in VLDL assembly in the HepG2 model., MEK1 exports PPARgamma from the nucleus, and this finding was supported by small interfering RNA knockdown of MEK1 and use of a cell-permeable interaction-blocking peptide, which prevented tetradecanoyl phorbol acetate-induced export of PPARgamma., mutational analysis of KRAS, BRAF, and MAP2K1/2 in 56 patients with CFC syndrome; comparison of the genotype-phenotype correlation of CFC with that of Costello syndrome suggest a significant clinical overlap but not genotype overlap., Mek1/2 are functionally redundant in the epidermis, where they act as a linear relay in the MAPK pathway to mediate development and homeostasis., These results indicated that the activation of CXCR4 and its signaling pathways (MEK1/2 and Akt) are essential for CXCL12-induced cholangiocarcinoma cell invasion., 3 novel mutations for MEK2 (L46_E55del, K61T, A62P) were identified in 15 patients with cardio-facio-cutaneous syndrome., study reports data concerning the biochemical functions of novel MEK1 and MEK2 mutants found in patients with cardio-facio-cutaneous syndrome, as well as the roles of these genes in the MAPK signaling cascade, the results of HRAS, BRAF and MAP2K1/2 mutation screening in a large cohort of patients with CS and CFC, BRAF and MEK1/2 mutations may be more common than anticipated in ovarian cancer which could have important implications for treatment of patients with this disease and suggests potential new therapeutic avenues, Phase I trial of MEK1/2 inhibitor AZD6244 in tumor patients., study describes the biochemical characterization of novel BRAF and MEK germline mutations in cardio-facio-cutaneous syndrome, the induction of inflammatory genes by farnesol is mediated by the activation of the NF-kappaB pathway and involves MEK1/2-ERK1/2-MSK1-dependent phosphorylation of p65/RelA(Ser(276)), Esophageal cells from GERD patients with Barrett's esophagus have elevated MEK1 phosphorylation and decreased MEK1/MEK2 activity., MEK1 & MEK2 isoforms have similar transforming properties & are able to induce formation of metastatic intestinal tumors in mice; results suggest MEK2 plays a more important role than MEK1 in sustaining proliferation of human colorectal cancer cells, Spectrum of MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations, MEK1/2 phosphorylates ERK1/2, which phosphorylates Sp1 and AP-1 that in turn bind to their respective binding sites to regulate the expression of human VIL2 in ESCC cells., SGK1 expression during liver regeneration is a part of a signaling pathway that is necessary for enhancing ERK signaling activation through modulating the MEK/ERK complex formation., SDF-1alpha acts through CXCR4 to activate MEK and ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrins and contributing the migration of human osteosarcoma cells., Different mutations in the MAPK pathway play distinct roles in the growth and invasion of thyroid cancer cells, Investigated the prevalence of PTPN11, HRAS, KRAS, NRAS, BRAF, MEK1, and MEK2 mutations in a relatively large cohort of primary embryonal Rhabdomyosarcoma (RMS) tumors. No mutation was observed in BRAF and MEK genes., Data show that oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition., This study demonstrated that H. pylori LPS may be a pathogenic factor causing gastric tumors by enhancing cell proliferation and inflammation via the MAPK cascade in gastric epithelial cells., These results demonstrate that MEK1 and MEK2 act differently and that herpes simplex virus type 2 hijacks host MEK1 for its own amplification., This first reported case of a vertically transmitted functional Cardio-facio-cutaneous syndrome MEK mutation., MEK1 and MEK2 play a part in the induction of the proinflammatory cytokine., Apoptosis induction by MEK1/2 inhibition in human lung cancer cells is mediated by Bim., familial inheritance of cardiofaciocutaneous syndrome with MEK2 mutation, In the absence of other MKK, MEK2 is sufficient for SK-MEL-28 cell proliferation and anchorage-dependent growth., ETS1 is probably mediating high CIP2A expression in human cancers with increased EGFR-MEK1/2-ERK pathway activity, Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells., Data show that mitogen-activated protein kinase kinases direct mitochondrial biogenesis by selectively inducing PGC-1beta expression., Data report the full-length structure of MEK2 obtained by homology modeling and molecular dynamics simulations., hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway., Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b., LPS increased IL-8 and IL-6 and decreased EVT invasion through activation of MEK1/2 MAPK signaling, E-cadherin is necessary for localization of DLG1 but not phosphorylated MEK2 to the midbody ring during cytokinesis., Screening a cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%., Findings indicate that Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef., Define the maximum tolerated dose and recommended phase 2 dose of MEK1/2 inhibitor trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours., Data show substantial clinical activity of MEK1/2 inhibitor trametinib in melanoma and suggest that MEK is a valid therapeutic target., C-MYC as a key driver of cell proliferation downstream of RAF-->MEK1/2-->ERK signaling., MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2., IL1beta treatment reduces SHBG production in HepG2 cells by the down-regulation of HNF-4A via the MAPK kinase (MEK)-1/2 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways., osteosarcoma patients whose tumors expressed pMEK2 had a poorer clinical outcome than those whose tumors did not., Data indicate that of the 32 cardio-facio-cutaneous syndrome (CFC) patients, 28 (88%) had a known mutation in a gene that is causative for CFC, including BRAF (n = 21), MEK1 (n = 2), MEK2 (n = 4), and KRAS (n = 1)., JTP-74057 is a novel MEK1/2 inhibitor able to sustain MEK in an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation., Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies., Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in malignant peripheral nerve sheath tumor cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway., Report a synthetic lethal interaction between PI3K/mTOR and MEK inhibitors in rhabdomyosarcoma., Data indicate that dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective approach to treating ovarian cancer., we report familial patients with multiple cafe au lait spots and Noonan syndrome-like facial features who carried mutations in MAP2K2., our data emphasizes the importance of the translational regulation of p21 by the MEK1/2-ERK1/2-p70S6K pathway to negatively control the cell cycle progression., Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction., CCR7 can also promote survival of mDCs through a novel MEK1/2-ERK1/2-AMPK signaling axis., We documented three novel mutations in the BRAF gene in cardio-facio-cutaneous syndrome patients and correlated clinical findings with causative mutations in the BRAF or MEK1/MEK2 genes, We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene., MEK1/2 inhibitor trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive non-small cell lung carcinoma., MK2 attenuates dendritic cell-mediated Th1 differentiation and autoimmune encephalomyelitis., at clinically relevant concentrations, cDDP binds to and inhibits MEK1/2 and both the binding and inhibitory activity are related to its interaction with Cu bound to MEK1/2, MEK1 levels are upregulated at transcriptional level whereas MEK2 levels are downregulated at posttranslational level., Endocytosis separates EGF receptors from endogenous fluorescently labeled HRas and diminishes receptor signaling to MAP kinases in endosomes.,
OMIM_DISEASE Cardiofaciocutaneous syndrome 4,
SP_COMMENT catalytic activity:ATP + a protein = ADP + a phosphoprotein., disease:Defects in MAP2K2 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., function:Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases., PTM:MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1)., similarity:Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily., similarity:Contains 1 protein kinase domain., subunit:Interacts with MORG1.,