Genomes and Genes
map kinase kinase 1
Summary: An abundant 43-kDa mitogen-activated protein kinase kinase subtype with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.
- Chen G, Ghosh P, Longo D. Distinctive mechanism for sustained TGF-Î² signaling and growth inhibition: MEK1 activation-dependent stabilization of type II TGF-Î² receptors. Mol Cancer Res. 2011;9:78-89 pubmed publisher..Collectively, our data suggest a novel mechanism for MEK1 in regulating the sensitivity to TGF-Î² signaling by stabilizing TÎ²RII. ..
- Yoon J, Koo K, Choi K. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res. 2011;71:445-53 pubmed publisher..Our findings offer proof-of-concept for the use of MEK inhibitors as an effective therapy in K-ras mutated CRC. ..
- Meng J, Fang B, Liao Y, Chresta C, Smith P, Roth J. Apoptosis induction by MEK inhibition in human lung cancer cells is mediated by Bim. PLoS ONE. 2010;5:e13026 pubmed publisher..These results have implications in the development of strategies to overcome resistance to MEK inhibitors. ..
- Wu H, Ho H, Burgess S. Mek1 kinase governs outcomes of meiotic recombination and the checkpoint response. Curr Biol. 2010;20:1707-16 pubmed publisher..We discuss how regulation of pachytene exit by Mek1 or similar kinases could influence checkpoint stringency, which may differ among species and between sexes. ..
- Morand S, Renggli C, Roditi I, Vassella E. MAP kinase kinase 1 (MKK1) is essential for transmission of Trypanosoma brucei by Glossina morsitans. Mol Biochem Parasitol. 2012;186:73-6 pubmed publisherb>MAP kinase kinase 1 (MKK1) is encoded by a single copy gene in Trypanosoma brucei. It has been shown recently that MKK1 is not essential for bloodstream forms ...
- Infante J, Fecher L, Falchook G, Nallapareddy S, Gordon M, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773-81 pubmed publisher..Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. GlaxoSmithKline. ..
- Meissner J, FREUND R, Krone D, Umeda P, Chang K, Gros G, et al. Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/beta gene expression via acetylation of nuclear factor of activated T cells c1. Nucleic Acids Res. 2011;39:5907-25 pubmed publisher..In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca(2+)-induced MyHCI/? expression. ..
- Roskoski R. MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun. 2012;417:5-10 pubmed publisher..MEK1 regulation is unusual in that S212 phosphorylation in its activation segment is inhibitory. Moreover, active ERK catalyzes a feedback inhibitory phosphorylation of MEK1 T292 that serves to downregulate the pathway. ..
- O Neil B, Goff L, Kauh J, Strosberg J, Bekaii Saab T, Lee R, et al. Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2011;29:2350-6 pubmed publisher..CONCLUSION In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation. ..
- Kirkwood J, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555-67 pubmed publisher..Five of six patients with partial response to selumetinib had BRAF mutant tumors. ..
- Heinrich M, Baldwin I, Wu J. Two mitogen-activated protein kinase kinases, MKK1 and MEK2, are involved in wounding- and specialist lepidopteran herbivore Manduca sexta-induced responses in Nicotiana attenuata. J Exp Bot. 2011;62:4355-65 pubmed publisher..The findings underscore the complexity of MAPK signalling pathways and highlight the importance of MAPKKs in regulating wounding- and herbivory-induced responses...
- Ho A, Grewal R, Leboeuf R, Sherman E, Pfister D, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:623-32 pubmed publisher..Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.). ..
- Jo C, Cho S, Jo S. Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes MyoD through direct phosphorylation at tyrosine 156 during myogenic differentiation. J Biol Chem. 2011;286:18903-13 pubmed publisher..Collectively, our results suggest that MEK1 activated in differentiating myoblasts stimulates muscle differentiation by phosphorylating MyoD-Y156, which results in MyoD stabilization. ..
- Ho H, Burgess S. Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis. PLoS Genet. 2011;7:e1002351 pubmed publisher..In addition, Xrs2, like Pch2, is required for checkpoint-mediated delay conferred by the failure to synapse chromosomes...
- Nikolaev S, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet. 2011;44:133-9 pubmed publisher..Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1. ..
- Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-14 pubmed publisher..Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.). ..
- Meng D, Lynch M, Huston E, Beyermann M, Eichhorst J, Adams D, et al. MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization. J Biol Chem. 2009;284:11425-35 pubmed publisher..In addition, the MEK disruptor peptide promoted the ability of betaarrestin1 to co-immunoprecipitate with endogenous c-Src and clathrin, facilitating the isoprenaline-stimulated internalization of the beta(2)-adrenergic receptor. ..
- Scholl F, Dumesic P, Barragan D, Charron J, Khavari P. Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene. 2009;28:1485-95 pubmed publisher..Thus, the effects of oncogenic Ras on proliferation and differentiation in skin show a gene dosage-dependent requirement for the Erk1/2 MAPK cascade at the level of Mek1/2 MAPKKs. ..
- Qiu J, Zhou L, Yun B, Nielsen H, Fiil B, Petersen K, et al. Arabidopsis mitogen-activated protein kinase kinases MKK1 and MKK2 have overlapping functions in defense signaling mediated by MEKK1, MPK4, and MKS1. Plant Physiol. 2008;148:212-22 pubmed publisher..In addition, transcriptome analyses delineate overlapping and specific effects of the kinases on global gene expression patterns demonstrating both redundant and unique functions for MKK1 and MKK2. ..
- Catalanotti F, Reyes G, Jesenberger V, Galabova Kovacs G, de Matos Simoes R, Carugo O, et al. A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol. 2009;16:294-303 pubmed publisher..Our data establish Mek1 as the crucial modulator of Mek and Erk signaling and have potential implications for the role of Mek1 and Mek2 in tumorigenesis. ..
- Gretton S, Hughes M, Harris M. Hepatitis C virus RNA replication is regulated by Ras-Erk signalling. J Gen Virol. 2010;91:671-80 pubmed publisher..However, complete inhibition of Ras-Erk signalling is inhibitory. These results suggest that perturbation of this signalling pathway by NS5A may be a mechanism to regulate levels of genomic RNA replication. ..
- Bric A, Miething C, Bialucha C, Scuoppo C, Zender L, Krasnitz A, et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell. 2009;16:324-35 pubmed publisher..Our results emphasize the utility of in vivo RNAi screens, identify and validate a diverse set of tumor suppressors, and have therapeutic implications. ..
- Nadeau V, Guillemette S, Bélanger L, Jacob O, Roy S, Charron J. Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development. 2009;136:1363-74 pubmed publisher..Thus, even though Map2k1 plays a predominant role, these results enlighten the function of Map2k2 in placenta development. ..
- Walker T, Mitchell C, Park M, Yacoub A, Rahmani M, Haussinger D, et al. 17-allylamino-17-demethoxygeldanamycin and MEK1/2 inhibitors kill GI tumor cells via Ca2+-dependent suppression of GRP78/BiP and induction of ceramide and reactive oxygen species. Mol Cancer Ther. 2010;9:1378-95 pubmed publisher
- Emery C, Vijayendran K, Zipser M, Sawyer A, Niu L, Kim J, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009;106:20411-6 pubmed publisher..These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications. ..
- Daouti S, Higgins B, Kolinsky K, Packman K, Wang H, Rizzo C, et al. Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models. Mol Cancer Ther. 2010;9:134-44 pubmed publisher..This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen. ..
- Marks J, Gong Y, Chitale D, Golas B, McLellan M, Kasai Y, et al. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res. 2008;68:5524-8 pubmed publisher..MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma. ..
- Yoon Y, Kim H, Han S, Hur H, Oh D, Im S, et al. Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. Mol Cancer Ther. 2009;8:2526-36 pubmed publisher..Our results provide the basis for a rational combination strategy against human EGFR WT gastric cancers, predicated on the understanding of cross-talk between the MEK and EGFR pathways. ..
- Voisin L, Julien C, Duhamel S, Gopalbhai K, Claveau I, Saba El Leil M, et al. Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer. 2008;8:337 pubmed publisher..Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells. ..
- Kim K, Kong S, Fulciniti M, Li X, Song W, Nahar S, et al. Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. Br J Haematol. 2010;149:537-49 pubmed publisher..Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome. ..
- Fischmann T, Smith C, Mayhood T, Myers J, Reichert P, Mannarino A, et al. Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry. 2009;48:2661-74 pubmed publisher..Finally, the structure provides for the first time a molecular rationale that explains how mutations in MEK may lead to the cardio-facio-cutaneous syndrome. ..
- Nada S, Hondo A, Kasai A, Koike M, Saito K, Uchiyama Y, et al. The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. EMBO J. 2009;28:477-89 pubmed publisher..These results indicate that the lipid raft adaptor p18 is essential for anchoring the MEK-ERK pathway to late endosomes, and shed new light on a role of endosomal MEK-ERK pathway in controlling endosome dynamics. ..
- Henderson Y, Chen Y, Frederick M, Lai S, Clayman G. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2010;9:1968-76 pubmed publisher..Our findings support the clinical evaluation of PD0325901 for patients with PTC and potentially other carcinomas with BRAF mutations. ..
- Yano M, Ikeda M, Abe K, Kawai Y, Kuroki M, Mori K, et al. Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal-regulated kinase. Hepatology. 2009;50:678-88 pubmed publisher..This intracellular modulation is expected to be a therapeutic target for the suppression of HCV RNA replication. ..
- Lemieux E, Bergeron S, Durand V, Asselin C, Saucier C, Rivard N. Constitutively active MEK1 is sufficient to induce epithelial-to-mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis. Int J Cancer. 2009;125:1575-86 pubmed publisher..In conclusion, our results demonstrate, for the first time, that constitutive activation of MEK1 in intestinal epithelial cells is sufficient to induce an EMT associated with tumor invasion and metastasis. ..
- Hennig M, Yip Schneider M, Klein P, Wentz S, Matos J, Doyle C, et al. Ethanol-TGFalpha-MEK signaling promotes growth of human hepatocellular carcinoma. J Surg Res. 2009;154:187-95 pubmed publisher..Ethanol-MEK signaling in normal hepatocytes is absent, suggesting that ethanol promotion of HCC growth may in part depend upon the acquisition of cancer-specific signaling by hepatocytes. ..
- Daouti S, Wang H, Li W, Higgins B, Kolinsky K, Packman K, et al. Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy. Cancer Res. 2009;69:1924-32 pubmed publisher..The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. ..
- Iverson C, Larson G, Lai C, Yeh L, Dadson C, Weingarten P, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009;69:6839-47 pubmed publisher..RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile...
- Banerji U, Camidge D, Verheul H, Agarwal R, Sarker D, Kaye S, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613-23 pubmed publisher..The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials. ..
- Yang J, Chang C, Xia W, Wang Y, WONG K, Engelman J, et al. Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. Cancer Res. 2010;70:4709-18 pubmed publisher..Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors. ..
- Tang Y, Sun F, Li X, Zhou Y, Yin S, Zhou X. Porphyromonas endodontalis lipopolysaccharides induce RANKL by mouse osteoblast in a way different from that of Escherichia coli lipopolysaccharide. J Endod. 2011;37:1653-8 pubmed publisher..The receptor activator of nuclear factor-?B ligand (RANKL) has been proven to be the key regulator of bone remodeling. This study investigated P. endodontalis LPS-induced RANKL production and LPS signaling in mouse osteoblasts...
- Sung J, Cho E, Cho J, Won C, Kim M, Koh P. Identification of proteins regulated by ferulic acid in a middle cerebral artery occlusion animal model-a proteomics approach. J Vet Med Sci. 2012;74:1401-7 pubmed..Thus, these findings suggest evidence that ferulic acid plays a neuroprotective role against focal cerebral ischemia through the up- and down-modulation of specific enzymes. ..
- Kumar V, Schuck E, Pelletier R, Farah N, Condon K, Ye M, et al. Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species. Cancer Chemother Pharmacol. 2012;69:229-37 pubmed publisher..In vitro results suggested that E6201 has low risk of drug-drug interactions due to CYP inhibition and induction in humans. In the first-in-man study, E6201 exhibited high clearance, which was well predicted by allometric scaling. ..
- Zou C, Chen Y, Smith R, Snavely C, Li J, Coon T, et al. SCF(Fbxw15) mediates histone acetyltransferase binding to origin recognition complex (HBO1) ubiquitin-proteasomal degradation to regulate cell proliferation. J Biol Chem. 2013;288:6306-16 pubmed publisher..These studies authenticate Fbxw15 as a ubiquitin E3 ligase subunit that mediates endotoxin-induced HBO1 depletion in cells, thereby controlling cell replicative capacity. ..
- Leicht D, Balan V, Zhu J, Kaplun A, Bronisz A, Rana A, et al. MEK-1 activates C-Raf through a Ras-independent mechanism. Biochim Biophys Acta. 2013;1833:976-86 pubmed publisher..This mechanism could be of significance in pathological conditions or cancers overexpressing C-Raf and MEK or in conditions where C-Raf-MEK interaction is enhanced due to the down-regulation of RKIP and MST2. ..
- Qin X, Qu X, Coy D, Weber H. A selective human bombesin receptor subtype-3 peptide agonist mediates CREB phosphorylation and transactivation. J Mol Neurosci. 2012;46:88-99 pubmed publisher..Thus, our results suggest that hBRS-3 agonist-dependent signaling mediates CREB phosphorylation and transactivation through partially PKA, PKC, and MEK-1 pathways. ..
- Tang Y, Dai Y, Grant S, Dent P. Enhancing CHK1 inhibitor lethality in glioblastoma. Cancer Biol Ther. 2012;13:379-88 pubmed publisher..These findings argue that multiple inhibitors of the SRC-MEK pathway have the potential to interact with multiple CHK1 inhibitors to kill glioma cells. ..
- Ju S, Goh A, Kwon D, Youn G, Kwon H, Bae Y, et al. Extracellular HIV-1 Tat induces human beta-defensin-2 production via NF-kappaB/AP-1 dependent pathways in human B cells. Mol Cells. 2012;33:335-41 pubmed publisher..Taken together, our results indicate that HIV-1 Tat can up-regulate the expression of hBD-2 via JNK-NF-?B/AP-1-dependent pathways in human B cells. ..