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 1(MAP2K1) mitogen-activated protein kinase kinase 1(MAP2K1) Related Genes Homo sapiens
CHROMOSOME 15,
CYTOBAND 15q22.1-q22.33,
ENSEMBL_GENE_ID ENSG00000169032,
GENERIF_SUMMARY MEK1 interacts with and phosphorylates ERK2. This interaction is mediated via a conserved N-terminal docking site in MEK1. Note that this interaction was demonstrated using rat ERK2., MEK1 interacts with ERK1. This interaction is mediated via a conserved N-terminal docking site in MEK1., Laminin-10/11 and fibronectin differentially prevent apoptosis induced by serum removal via phosphatidylinositol 3-kinase/Akt- and MEK1/ERK-dependent pathways (Laminin 10; separate entry for Laminin 11)., PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway, MEK1 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 MEK1 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., MEK1 has an activation domain that forms a hydrophobic binding pocket for enzyme inhibitor PD184352, Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways, the NH(2)-terminal end of MEK is important not only for substrate interaction but also for catalytic activity, 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., the dramatic activation of an endomembrane-associated MEK1 without the corresponding activation of the MEK substrate ERK during normal G(2)/M, 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, serum stimulation of fibroblasts in floating matrices does not result in ERK translocation to the nucleus. In addition, there was decreased serum activation of upstream members of the ERK signaling pathway, MEK and Raf, The 1,25(OH)(2)D3-responsive element in cystatin A gene is identical to TRE, T2 (-272 to -278). Suppression of Raf-1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of normal human keratinocytes., Inhibition of the upstream MAPK kinase inhibited the phosphorylation of ERK; modulated the levels of Bcl-2, Mcl-1, and cFLIP; and induced G2M cell-cycle arrest or apoptosis, Distribution of total MEK1 between Alzheimer disease[AD] and age-matched control cases was similar but increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD, results show that p38-mediated dephosphorylation of MEK1,2 mediates initiation of apoptosis, constituitively activated in choroidal melanoma cell lines, independent of Ras, and regulated by B-RafV599E, RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity., 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-., Glycogen synthase kinase-3beta is tyrosine-phosphorylated by mitogen-activated protein kinase kinase 1 in fibroblasts., Plk3 may be a key protein kinase mediating MEK1 function in the Golgi fragmentation pathway during cell division., in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFkappaB-independent, IL-8 and MIP3alpha expression., 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., Detailed pathway analysis revealed that BM stromal cells stimulate STAT3 via the IL-6R, and MEK1/ERK1 pathways, via IL-6R-independent mechanisms, Arsenic trioxide and inhibitors of this enzyme my be combined as anticancer agents for acute promyelocytic leukemia., 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, Integrin alphav controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling., MEK1 facilitates ligand-initiated transcriptional activation while targeting the Ah receptor for degradation, Blockade of MEK1 by PD98059 suppresses c-Fos and Fra-1 expression and, thus, affects two counteractive signals for IL-8 mRNA., Selesctive inhibitors potentiate apoptosis induction by sulindac sulfide, an NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer., The induction of the raf-1/MEK1 pathway blocks IGF-1-mediated intracellular neuroendocrine hormone regulation. This pathway may be a therapeutic target in gastrointestinal carcinoid tumor therapy., whereas MAPKK-1 signaling is required for VEGF synthesis only and PI3K activation activity was lowered in hypoxia., RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5, Cdc2 inhibits growth factor receptor-mediated ERK activation during mitosis by primarily targeting signaling proteins that are upstream of MEK1, The ability of constitutively-active human MEK1 to stimulate ERK phosphorylation and to induce the neoplastic transformation of NIH 3T3 cells required the integrity of the D-site was found., results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop, PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1, 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, Results describe the roles of MEK1/ERK and AKT/PKB pathways on the effects of granulocyte macrophage colony-stimulating factor (GM-CSF) and M-CSF on tumor progression of lung cancer., REVIEW. surprises yielded by the analysis of the role of B-Raf and Raf-1 and of their downstream effectors using conditional knockouts, 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., Our data suggest that overexpression of TNFalpha leads to topical GC insensitivity by reducing GR nuclear translocation in keratinocytes., 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., MEK1 plays an in vivo role in Golgi reorganization, which regulates cell cycle progression., Further studies confirm that promoter activity correlates with protein expression by demonstrating reduced SMAD3 protein expression in A549 cells and airway smooth muscle cells after treatment with MEK1 inhibitors., allosteric inhibitors have a dynamic range in the type of MEK1 activation states and nucleotide complexes that they can bind., 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., analysis of the ATPase activity of phospho-MEK-1 uncoupled from downstream ERK phosphorylation, WNK2 is involved in the modulation of growth factor-induced cancer cell proliferation through the MEK1/ERK1/2 pathway., 3 novel mutations for MEK1 (E44G, T55P, D67N) were found in cardio-facio-cutaneous syndrome. A novel mutation in exon 2 was found in Noonan syndrome., modulation of phosphatidylinositol 3-kinase/Akt/GSK3beta signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEK1 activity for proliferation., 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, Has a role in epithelial cell proliferation and lung remodeling after toxic injury., 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)), MEK1/ERK regulation of GRASP55-mediated Golgi linking is a control point in cell cycle progression, MEK1 is the critical isoform regulating tumor cell proliferation in vitro and in vivo., WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation., Esophageal cells from GERD patients with Barrett's esophagus have elevated MEK1 phosphorylation and decreased MEK1/MEK2 activity., analysis of the MEK1 mutation in lung adenocarcinoma, the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2, 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, active CaMKII directly phosphorylates MEK1 in vitro, which could be abrogated by CaMKII inhibitor, MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization, Spectrum of MEK1 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., TNF-alpha abrogated TGFbeta1-induced SMalphaA gene expression at the level of transcription without disrupting phosphorylation of regulatory Smads., activation of MEK1 selectively down-regulates human rhinovirus-induced expression of CXCL10 via modulation of IFN regulatory factor-1 interactions with the gene promoter in human airway epithelial cells, One MAP kinase kinase 1 mutation is found in 1 of 37 melanoma tumor samples and another MEK1 mutation in 1 of 45 colon cancer samples., 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., Different mutations in the MAPK pathway play distinct roles in the growth and invasion of thyroid cancer cells, Data provide a basis for rational combination of MEK and PI3K inhibitors in basal-like cancers with both intact and deleted PTEN., Meaasurement of ERK 1/2 in csf from patients iwht neuropsychiatric disorders and evidence for the presence of the activated form., 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 in hypoxic conditions or coexpressed with a constitutively active form of HIF-1alpha, c-Kit mutants activate the Ras/Raf/Mek/Erk pathway, stimulate proliferation and transform melanocytes., Data show that oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition., In suicide brain, the interaction of MEK1 with ERK1 and ERK2 is increased along with decreased phosphorylation and catalytic activity of ERK1/2., 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., Data show that the FGF2-induced ERK MAP kinase strongly increased the Runx2 protein level through an increase in acetylation and a decrease in ubiquitination., These results demonstrate that MEK1 and MEK2 act differently and that herpes simplex virus type 2 hijacks host MEK1 for its own amplification., Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2alpha signaling in breast cancer., results show that PMA activates the MEK-ERK pathway and strongly induces miRNA-34a expression, which in turn inhibits cell proliferation by repressing the expression of MEK1, MEK1 mutations exclusive with EGFR, K-ras, and B-raf mutations at kinase domain is associated with lung cancer., SH3GL2 participates in the regulation of apoptosis through the MEK-ERK signal pathway by adjusting EGFR in the laryngeal carcinoma cell line Hep2, The C-terminal ILLHPWF motif that is well conserved among Trib family proteins is required for MEK1 binding, enhancement of ERK phosphorylation, enhanced self-renewal activity of bone marrow cells and leukemogenic activity by Trib1., Here, the authors show that an MEK-cofilin signalling module has an important function for the migration of human T cells in 3D environments., Apoptosis induction by MEK1/2 inhibition in human lung cancer cells is mediated by Bim., We have uncovered an IL-2- and IL-4-driven MEK1 induction mechanism that results in heightened ERK1/2 activation in asthmatic T cells, Nek10 physically associated with Raf-1 and MEK1 in a Raf-1-dependent manner, and the formation of this complex was necessary for Nek10-mediated MEK1 activation., Data suggest a novel mechanism for MEK1 in regulating the sensitivity to TGF-beta signaling by stabilizing TbetaRII., decreased mir-424 expression and increased levels of MEK1 or cyclin E1 in senile hemangioma may cause abnormal cell proliferation in the tumor, oncogenic Ras efficiently activates the ERK pathway both by activating Raf and by inhibiting MEK SUMOylation, thereby inducing carcinogenesis, Thus, MEK1(C121S) or functionally similar mutations are predicted to confer drug resistance of neoplasms to combined MEK/RAF inhibition., 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., These results suggest the regulatory role of MEK in TIM-3 transcription by human CD4+ T cells and mast cells, In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets, These findings suggest that the upregulation of PGRN via the p38MAPK and MEK1/2 signaling pathway in Helicobacter pylori-infected gastric epithelial cells may contribute to the carcinogenic process., TGF-beta1 undergo a switch into mesenchymal cells and PI3K/Akt and MAPK/Erk1/2 signaling pathways serve to regulate TGF-beta1-induced epithelial-to-mesenchymal transition of A549 cells., The BRAF/MEK/ERK pathway is upregulated in progressive retinal arterial macroaneurysm patients, caused by mutation in IGFBP7., conclude that graded increases in the MEK1 signaling module are correlated with M1-MMP expression, renal epithelial cell tumor phenotype, invasive activity and nuclear grade, the activation of PI3K and MEK pathways is not the only mechanism of EGFR-resistance, LPS increased IL-8 and IL-6 and decreased EVT invasion through activation of MEK1/2 MAPK signaling, Our data suggest that the miR-1826 plays an important role as a tumor suppressor by downregulating beta-catenin and MEK1 in von Hippel-Lindau-inactivated renal cancers., These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer., 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%., The induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling., Findings indicate that Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef., A total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors., Inhibition of extracellular signal regulated kinase 1/2 and c-jun N-terminal kinases increases, but that inhibition of p38 mitogen-activated protein kinase decreases M. tuberculosis-induced CD44 surface expression in THP-1 human monocytes., These data indicate that MED28 regulates cellular migration in a MEK1-dependent manner in human breast cancer cells, reinforcing the important cellular roles of MED28., These results suggest that EGF is secreted from A549 cells by MMP and increases claudin-2 expression mediated via the activation of an EGFR/MEK/ERK pathway., Activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAF inhibitor resistance in melanoma., observed that, although MEK1 negatively regulates TLR2 signaling in EC, MEK1 promotes TLR2 signaling in monocytes, VRK2A can form a high molecular size complex with both MEK1 and KSR1; the KSR1 complex assembled and retained by VRK2A in the endoplasmic reticulum can have a modulatory effect on the signal mediated by MAPK,locally affecting the magnitude of its responses, Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1., a Ras-Raf-MEK1, but not MEK2, signaling cascade is necessary and sufficient for Erk2 nuclear localization that works in concert with TGF-beta to promote EMT., 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., 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 pMEK1 had a poorer clinical outcome than those whose tumors did not., integrin-triggered, RIAM-dependent MEK activation represents a key feedback event required for efficient focal adhesion disassembly., 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)., These data show that the MAPK-ERK pathway plays an important role in the regulation of hepatitis C virus gene expression and replication., DiRas3 interacts with C-RAF and downregulates MEK1 activity to restrict cell migration., A novel nuclear function of MEK1 triggers a complex pattern of early T cell activation, followed by a late inhibition through its interaction with silencing mediator of retinoid and thyroid hormone receptor (SMRT)., 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., Myt1 is inactivated by MEK1 mediated phosphorylation to fragment the Golgi complex in G2 and for the entry of cells into mitosis., The ability of MEK to activate C-Raf was only partially dependent on MEK kinase activity but required MEK binding to C-Raf, suggesting that the binding results in a conformational change that increases C-Raf susceptibility to phosphorylation, 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., MEK1 is a novel outcome for signalling through the canonical MAPK pathway that is a naturally occurring,pathway regulated dominant negative to block signalling to ERK-p90RSK, Report a synthetic lethal interaction between PI3K/mTOR and MEK inhibitors in rhabdomyosarcoma., Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors, Data show that hepatitis C virus NS5A-transactivated protein 9 (NS5ATP9) knockdown activated mitogen-activated protein kinase kinase/extracellular signal regulated kinases 1/2 signaling under C virus nonstructural protein 5A (NS5A) expression., genetic association study in Han population in China, Authors demonstrate that HIV-1 Nef expression mediates phosphorylation of Mek1 on serine298 and Pak2 on serine192/197 in T cell lines as well as primary human T cells., inhibition of MEK partially inhibited MTOR in a cell-type-dependent manner, activation of RAF1-MEK1-ERK/AKT axis may determine the resistance of non-small cell lung cancer cell lines bearing wild type EGFR to erlotinib, 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., Phosphorylated-FAKSer732 was barely detectable during interphase while its levels strongly increased in mitotic cells upon activation of the EGFR/MEK/ERK/CDK5 axis in an integrin-independent manner., Combined therapy targeting both MEK and STAT3, but not either single pathway, resulted in complete regression of selumetinib-resistant tumors, MEK1-YAP interaction is critical for liver cancer cell proliferation and maintenance of transformed phenotypes both in vitro and in vivo., high frequency of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias., Studies suggest that MAP Kinase Kinase 1 (MEK1) inhibitors represent a new treatment option in BRAF and NRAS mutated melanoma., Activated MEK1 is associated with chordoma., 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., Treatment of cells with sirtuin inhibitors, or siRNA knockdown of SIRT1 or SIRT2 proteins, increases MEK1 acetylation and subsequent phosphorylation of the extracellular signal-regulated kinase., Findings support the hypothesis that BDNF and MEK1 mRNA expression levels are more obviously decreased in patients with treatment-resistant depression., Data indicate that combined PI3K inhibitor LY294002 and mitogen activated protein kinase kinase (MEK) inhibitor AZD6244 showed synergistic effect on inhibition of SKOV3/DDP cell growth by inducing apoptosis and blocking cell cycle., This is the first report of MAP2K1 mutations in Langerhans cell histiocytosis(LCH) that occur in 50% of BRAF wild-type cases. The mutually exclusive nature of MAP2K1 and BRAF mutations implicates a critical role of oncogenic MAPK signaling in LCH., X-ray crystallography reveals a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK., Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation., MAP2K1 missense mutations were found in 2 of 11 patients with cadiofaciocutaneous syndrome, 33% of Langerhans cell histiocytosis cases with wild-type BRAF and none with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro., MEK1 mutations define a distinct subset of lung cancers ( approximately 1%) with potential sensitivity to MEK inhibitors. Mutations are predominantly transversions, in keeping with a strong association with smoking., our data indicate that preexisting MEK1(P124) mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies, MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer., 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, Findings establish that the convergence of 2 distinct Ras effector pathways on mammalian target of rapamycin signaling maintains neurofibromatosis type 1 mouse optic glioma growth., MEK1/2 inhibitor potentiated the anti-tumor effects of cisplatin in KRAS-dependent lung cancer cells and an animal model through inhibition of BIM degradation, Data show that licochalcone A (LicoA) suppresses solar UV-induced cyclooxygenase (COX-2) expression by acting as a potent inhibitor of enzymes PI3K, MEK1, and B-Raf., Data indicate that cyclic AMP signaling reduces the expression of sirtuin 6 deacetylase via inhibition of the c-Raf-MEK1-ERK1/2 pathway., 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., Langerhans cell histiocytosis cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting., SGK1 inhibits intestinal epithelial cell apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis., Studies indicate that concurrent inhibition of proto-oncogene protein B-raf (BRAF) and Map kinase kinase (MEK) improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with metastatic melanoma (MM)., 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., Findings suggest that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma., MEK1 Mutations are associated with Low-grade Serous Ovarian Cancer., Data show that src kinases (SRC) and mitogen-activated protein kinase kinase 1 (MEK) co-inhibition by saracatinib and PD0325901 respectively can be broadly effective in tumor growth control of a wide panel of non-small cell lung cancer (NSCLC) cell lines., Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent., NOTCH1, TP53, and MAP2K1 mutations in splenic diffuse red pulp small B-cell lymphoma are associated with progressive disease., Data show that Ba/F3 cells transformed with mutant HRAS protien indicated equal sensitivity towards Map kinase kinase (MEK) and mTOR serine-threonine kinase (mTOR) inhibition., Endocytosis separates EGF receptors from endogenous fluorescently labeled HRas and diminishes receptor signaling to MAP kinases in endosomes., A-Raf interacts with MEK1 and activates MEK1 by phosphorylation., c-Raf interacts with MEK1 and activates MEK1 by phosphorylation., MEK1 interacts with B-Raf.,
OFFICIAL_GENE_SYMBOL MAP2K1,
OMIM_DISEASE Cardiofaciocutaneous syndrome 3,
SP_COMMENT catalytic activity:ATP + a protein = ADP + a phosphoprotein., 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., enzyme regulation:Activated by phosphorylation., function:Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates ERK1 and ERK2 MAP kinases., PTM:Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway., PTM:Phosphorylation on Ser/Thr by MAP kinase kinase kinases (RAF or MEKK1) regulates positively the kinase activity., similarity:Belongs to the protein kinase superfamily., 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 (By similarity). Interacts with Yersinia yopJ.,
mitogen-activated protein kinase kinase 2(MAP2K2) mitogen-activated protein kinase kinase 2(MAP2K2) Related Genes Homo sapiens
CHROMOSOME 19, 7,
CYTOBAND 19p13.3, 7q32.3,
ENSEMBL_GENE_ID ENSG00000126934,
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.,
OFFICIAL_GENE_SYMBOL MAP2K2,
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.,