Full text data of MAP2K2
MAP2K2
(MEK2, MKK2, PRKMK2)
[Confidence: low (only semi-automatic identification from reviews)]
Dual specificity mitogen-activated protein kinase kinase 2; MAP kinase kinase 2; MAPKK 2; 2.7.12.2 (ERK activator kinase 2; MAPK/ERK kinase 2; MEK 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Dual specificity mitogen-activated protein kinase kinase 2; MAP kinase kinase 2; MAPKK 2; 2.7.12.2 (ERK activator kinase 2; MAPK/ERK kinase 2; MEK 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P36507
ID MP2K2_HUMAN Reviewed; 400 AA.
AC P36507;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 2;
DE Short=MAP kinase kinase 2;
DE Short=MAPKK 2;
DE EC=2.7.12.2;
DE AltName: Full=ERK activator kinase 2;
DE AltName: Full=MAPK/ERK kinase 2;
DE Short=MEK 2;
GN Name=MAP2K2; Synonyms=MEK2, MKK2, PRKMK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8388392;
RA Zheng C.-F., Guan K.-L.;
RT "Cloning and characterization of two distinct human extracellular
RT signal-regulated kinase activator kinases, MEK1 and MEK2.";
RL J. Biol. Chem. 268:11435-11439(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PROTEIN SEQUENCE OF 40-51; 53-61; 64-100; 102-112; 164-172; 194-205;
RP 265-297; 362-371 AND 389-397, PHOSPHORYLATION AT THR-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Zebisch A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [4]
RP PROTEIN SEQUENCE OF 210-231, INACTIVATION BY YERSINIA YOPJ,
RP PHOSPHORYLATION AT SER-222 AND SER-226, ACETYLATION AT SER-222 AND
RP SER-226, AND MASS SPECTROMETRY.
RX PubMed=17116858; DOI=10.1073/pnas.0608995103;
RA Mittal R., Peak-Chew S.Y., McMahon H.T.;
RT "Acetylation of MEK2 and I kappa B kinase (IKK) activation loop
RT residues by YopJ inhibits signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006).
RN [5]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=9563949; DOI=10.1126/science.280.5364.734;
RA Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R.,
RA Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D.,
RA Vande Woude G.F.;
RT "Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal
RT factor.";
RL Science 280:734-737(1998).
RN [6]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/0264-6021:3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family
RT members to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293 AND SER-295, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP INTERACTION WITH SGK1.
RX PubMed=19447520; DOI=10.1016/j.jhep.2009.02.027;
RA Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J.,
RA Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M.,
RA Hur G.M.;
RT "Protein kinase SGK1 enhances MEK/ERK complex formation through the
RT phosphorylation of ERK2: implication for the positive regulatory role
RT of SGK1 on the ERK function during liver regeneration.";
RL J. Hepatol. 51:67-76(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-295 AND THR-394, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP VARIANT CFC4 CYS-57.
RX PubMed=16439621; DOI=10.1126/science.1124642;
RA Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A.,
RA Cruz M.S., McCormick F., Rauen K.A.;
RT "Germline mutations in genes within the MAPK pathway cause cardio-
RT facio-cutaneous syndrome.";
RL Science 311:1287-1290(2006).
RN [19]
RP VARIANTS CFC4 VAL-57 AND HIS-134.
RX PubMed=18042262; DOI=10.1111/j.1399-0004.2007.00931.x;
RA Schulz A.L., Albrecht B., Arici C., van der Burgt I., Buske A.,
RA Gillessen-Kaesbach G., Heller R., Horn D., Hubner C.A., Korenke G.C.,
RA Konig R., Kress W., Kruger G., Meinecke P., Mucke J., Plecko B.,
RA Rossier E., Schinzel A., Schulze A., Seemanova E., Seidel H.,
RA Spranger S., Tuysuz B., Uhrig S., Wieczorek D., Kutsche K., Zenker M.;
RT "Mutation and phenotypic spectrum in patients with cardio-facio-
RT cutaneous and Costello syndrome.";
RL Clin. Genet. 73:62-70(2008).
RN [20]
RP VARIANT CFC4 GLN-128, AND CHARACTERIZATION OF VARIANT CFC4 GLN-128.
RX PubMed=20358587; DOI=10.1002/ajmg.a.33342;
RA Rauen K.A., Tidyman W.E., Estep A.L., Sampath S., Peltier H.M.,
RA Bale S.J., Lacassie Y.;
RT "Molecular and functional analysis of a novel MEK2 mutation in cardio-
RT facio-cutaneous syndrome: transmission through four generations.";
RL Am. J. Med. Genet. A 152:807-814(2010).
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine
CC and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP
CC kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- SUBUNIT: Interacts with MORG1 (By similarity). Interacts with
CC SGK1.
CC -!- INTERACTION:
CC P10398:ARAF; NbExp=4; IntAct=EBI-1056930, EBI-365961;
CC Q12959:DLG1; NbExp=10; IntAct=EBI-1056930, EBI-357481;
CC -!- PTM: MAPKK is itself dependent on Ser/Thr phosphorylation for
CC activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1).
CC Phosphorylated by MAP2K1/MEK1 (By similarity).
CC -!- PTM: Acetylation of Ser-222 and Ser-226 by Yersinia yopJ prevents
CC phosphorylation and activation, thus blocking the MAPK signaling
CC pathway.
CC -!- DISEASE: Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: A
CC form of cardiofaciocutaneous syndrome, a multiple congenital
CC anomaly disorder characterized by a distinctive facial appearance,
CC heart defects and mental retardation. Heart defects include
CC pulmonic stenosis, atrial septal defects and hypertrophic
CC cardiomyopathy. Some affected individuals present with ectodermal
CC abnormalities such as sparse, friable hair, hyperkeratotic skin
CC lesions and a generalized ichthyosis-like condition. Typical
CC facial features are similar to Noonan syndrome. They include high
CC forehead with bitemporal constriction, hypoplastic supraorbital
CC ridges, downslanting palpebral fissures, a depressed nasal bridge,
CC and posteriorly angulated ears with prominent helices. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K2";
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DR EMBL; L11285; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC000471; AAH00471.1; -; mRNA.
DR EMBL; BC018645; AAH18645.1; -; mRNA.
DR PIR; A46723; A46723.
DR RefSeq; NP_109587.1; NM_030662.3.
DR UniGene; Hs.465627; -.
DR PDB; 1S9I; X-ray; 3.20 A; A/B=55-400.
DR PDB; 4H3Q; X-ray; 2.20 A; B=4-16.
DR PDBsum; 1S9I; -.
DR PDBsum; 4H3Q; -.
DR ProteinModelPortal; P36507; -.
DR SMR; P36507; 60-393.
DR DIP; DIP-29119N; -.
DR IntAct; P36507; 14.
DR MINT; MINT-99667; -.
DR STRING; 9606.ENSP00000262948; -.
DR BindingDB; P36507; -.
DR ChEMBL; CHEMBL2964; -.
DR GuidetoPHARMACOLOGY; 2063; -.
DR PhosphoSite; P36507; -.
DR DMDM; 547915; -.
DR REPRODUCTION-2DPAGE; IPI00003783; -.
DR PaxDb; P36507; -.
DR PeptideAtlas; P36507; -.
DR PRIDE; P36507; -.
DR DNASU; 5605; -.
DR Ensembl; ENST00000262948; ENSP00000262948; ENSG00000126934.
DR GeneID; 5605; -.
DR KEGG; hsa:5605; -.
DR UCSC; uc002lzj.3; human.
DR CTD; 5605; -.
DR GeneCards; GC19M004090; -.
DR H-InvDB; HIX0033655; -.
DR HGNC; HGNC:6842; MAP2K2.
DR HPA; CAB003835; -.
DR MIM; 601263; gene.
DR MIM; 615280; phenotype.
DR neXtProt; NX_P36507; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR PharmGKB; PA30587; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000234206; -.
DR HOVERGEN; HBG108518; -.
DR InParanoid; P36507; -.
DR KO; K04369; -.
DR OMA; RLKQPST; -.
DR OrthoDB; EOG7HF1KZ; -.
DR PhylomeDB; P36507; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P36507; -.
DR ChiTaRS; MAP2K2; human.
DR EvolutionaryTrace; P36507; -.
DR GeneWiki; MAP2K2; -.
DR GenomeRNAi; 5605; -.
DR NextBio; 21780; -.
DR PMAP-CutDB; P36507; -.
DR PRO; PR:P36507; -.
DR ArrayExpress; P36507; -.
DR Bgee; P36507; -.
DR CleanEx; HS_MAP2K2; -.
DR Genevestigator; P36507; -.
DR GO; GO:0005938; C:cell cortex; IEA:Ensembl.
DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0005769; C:early endosome; TAS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; TAS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; TAS:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; NAS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:2000147; P:positive regulation of cell motility; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB.
DR GO; GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB.
DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Cardiomyopathy;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Ectodermal dysplasia; Kinase; Mental retardation; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1 400 Dual specificity mitogen-activated
FT protein kinase kinase 2.
FT /FTId=PRO_0000086372.
FT DOMAIN 72 369 Protein kinase.
FT NP_BIND 78 86 ATP (By similarity).
FT COMPBIAS 266 315 Pro-rich.
FT ACT_SITE 194 194 Proton acceptor (By similarity).
FT BINDING 101 101 ATP (By similarity).
FT SITE 10 11 Cleavage; by anthrax lethal factor.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 222 222 O-acetylserine; by Yersinia yopJ;
FT alternate.
FT MOD_RES 222 222 Phosphoserine; by RAF; alternate.
FT MOD_RES 226 226 O-acetylserine; by Yersinia yopJ;
FT alternate.
FT MOD_RES 226 226 Phosphoserine; alternate.
FT MOD_RES 293 293 Phosphoserine.
FT MOD_RES 295 295 Phosphoserine.
FT MOD_RES 394 394 Phosphothreonine.
FT MOD_RES 396 396 Phosphothreonine.
FT VARIANT 57 57 F -> C (in CFC4).
FT /FTId=VAR_035095.
FT VARIANT 57 57 F -> V (in CFC4).
FT /FTId=VAR_069781.
FT VARIANT 128 128 P -> Q (in CFC4; results in increased
FT kinase activity).
FT /FTId=VAR_069782.
FT VARIANT 134 134 Y -> H (in CFC4).
FT /FTId=VAR_069783.
FT HELIX 69 71
FT STRAND 72 80
FT STRAND 85 91
FT TURN 92 94
FT STRAND 97 103
FT HELIX 110 119
FT HELIX 120 122
FT STRAND 133 148
FT HELIX 155 161
FT STRAND 162 164
FT HELIX 167 186
FT HELIX 197 199
FT STRAND 200 202
FT STRAND 208 210
FT HELIX 217 222
FT HELIX 236 239
FT HELIX 246 262
FT HELIX 272 279
FT HELIX 318 327
FT TURN 335 337
FT HELIX 340 349
FT TURN 354 356
FT HELIX 360 364
FT HELIX 367 374
FT HELIX 379 386
SQ SEQUENCE 400 AA; 44424 MW; 3401D522515C30A5 CRC64;
MLARRKPVLP ALTINPTIAE GPSPTSEGAS EANLVDLQKK LEELELDEQQ KKRLEAFLTQ
KAKVGELKDD DFERISELGA GNGGVVTKVQ HRPSGLIMAR KLIHLEIKPA IRNQIIRELQ
VLHECNSPYI VGFYGAFYSD GEISICMEHM DGGSLDQVLK EAKRIPEEIL GKVSIAVLRG
LAYLREKHQI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DSMANSFVGT RSYMAPERLQ
GTHYSVQSDI WSMGLSLVEL AVGRYPIPPP DAKELEAIFG RPVVDGEEGE PHSISPRPRP
PGRPVSGHGM DSRPAMAIFE LLDYIVNEPP PKLPNGVFTP DFQEFVNKCL IKNPAERADL
KMLTNHTFIK RSEVEEVDFA GWLCKTLRLN QPGTPTRTAV
//
ID MP2K2_HUMAN Reviewed; 400 AA.
AC P36507;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 2;
DE Short=MAP kinase kinase 2;
DE Short=MAPKK 2;
DE EC=2.7.12.2;
DE AltName: Full=ERK activator kinase 2;
DE AltName: Full=MAPK/ERK kinase 2;
DE Short=MEK 2;
GN Name=MAP2K2; Synonyms=MEK2, MKK2, PRKMK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8388392;
RA Zheng C.-F., Guan K.-L.;
RT "Cloning and characterization of two distinct human extracellular
RT signal-regulated kinase activator kinases, MEK1 and MEK2.";
RL J. Biol. Chem. 268:11435-11439(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PROTEIN SEQUENCE OF 40-51; 53-61; 64-100; 102-112; 164-172; 194-205;
RP 265-297; 362-371 AND 389-397, PHOSPHORYLATION AT THR-394, AND MASS
RP SPECTROMETRY.
RC TISSUE=Colon carcinoma;
RA Bienvenut W.V., Zebisch A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [4]
RP PROTEIN SEQUENCE OF 210-231, INACTIVATION BY YERSINIA YOPJ,
RP PHOSPHORYLATION AT SER-222 AND SER-226, ACETYLATION AT SER-222 AND
RP SER-226, AND MASS SPECTROMETRY.
RX PubMed=17116858; DOI=10.1073/pnas.0608995103;
RA Mittal R., Peak-Chew S.Y., McMahon H.T.;
RT "Acetylation of MEK2 and I kappa B kinase (IKK) activation loop
RT residues by YopJ inhibits signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006).
RN [5]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=9563949; DOI=10.1126/science.280.5364.734;
RA Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R.,
RA Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D.,
RA Vande Woude G.F.;
RT "Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal
RT factor.";
RL Science 280:734-737(1998).
RN [6]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/0264-6021:3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family
RT members to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293 AND SER-295, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP INTERACTION WITH SGK1.
RX PubMed=19447520; DOI=10.1016/j.jhep.2009.02.027;
RA Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J.,
RA Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M.,
RA Hur G.M.;
RT "Protein kinase SGK1 enhances MEK/ERK complex formation through the
RT phosphorylation of ERK2: implication for the positive regulatory role
RT of SGK1 on the ERK function during liver regeneration.";
RL J. Hepatol. 51:67-76(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-295 AND THR-394, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP VARIANT CFC4 CYS-57.
RX PubMed=16439621; DOI=10.1126/science.1124642;
RA Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A.,
RA Cruz M.S., McCormick F., Rauen K.A.;
RT "Germline mutations in genes within the MAPK pathway cause cardio-
RT facio-cutaneous syndrome.";
RL Science 311:1287-1290(2006).
RN [19]
RP VARIANTS CFC4 VAL-57 AND HIS-134.
RX PubMed=18042262; DOI=10.1111/j.1399-0004.2007.00931.x;
RA Schulz A.L., Albrecht B., Arici C., van der Burgt I., Buske A.,
RA Gillessen-Kaesbach G., Heller R., Horn D., Hubner C.A., Korenke G.C.,
RA Konig R., Kress W., Kruger G., Meinecke P., Mucke J., Plecko B.,
RA Rossier E., Schinzel A., Schulze A., Seemanova E., Seidel H.,
RA Spranger S., Tuysuz B., Uhrig S., Wieczorek D., Kutsche K., Zenker M.;
RT "Mutation and phenotypic spectrum in patients with cardio-facio-
RT cutaneous and Costello syndrome.";
RL Clin. Genet. 73:62-70(2008).
RN [20]
RP VARIANT CFC4 GLN-128, AND CHARACTERIZATION OF VARIANT CFC4 GLN-128.
RX PubMed=20358587; DOI=10.1002/ajmg.a.33342;
RA Rauen K.A., Tidyman W.E., Estep A.L., Sampath S., Peltier H.M.,
RA Bale S.J., Lacassie Y.;
RT "Molecular and functional analysis of a novel MEK2 mutation in cardio-
RT facio-cutaneous syndrome: transmission through four generations.";
RL Am. J. Med. Genet. A 152:807-814(2010).
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine
CC and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP
CC kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- SUBUNIT: Interacts with MORG1 (By similarity). Interacts with
CC SGK1.
CC -!- INTERACTION:
CC P10398:ARAF; NbExp=4; IntAct=EBI-1056930, EBI-365961;
CC Q12959:DLG1; NbExp=10; IntAct=EBI-1056930, EBI-357481;
CC -!- PTM: MAPKK is itself dependent on Ser/Thr phosphorylation for
CC activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1).
CC Phosphorylated by MAP2K1/MEK1 (By similarity).
CC -!- PTM: Acetylation of Ser-222 and Ser-226 by Yersinia yopJ prevents
CC phosphorylation and activation, thus blocking the MAPK signaling
CC pathway.
CC -!- DISEASE: Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: A
CC form of cardiofaciocutaneous syndrome, a multiple congenital
CC anomaly disorder characterized by a distinctive facial appearance,
CC heart defects and mental retardation. Heart defects include
CC pulmonic stenosis, atrial septal defects and hypertrophic
CC cardiomyopathy. Some affected individuals present with ectodermal
CC abnormalities such as sparse, friable hair, hyperkeratotic skin
CC lesions and a generalized ichthyosis-like condition. Typical
CC facial features are similar to Noonan syndrome. They include high
CC forehead with bitemporal constriction, hypoplastic supraorbital
CC ridges, downslanting palpebral fissures, a depressed nasal bridge,
CC and posteriorly angulated ears with prominent helices. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K2";
CC -----------------------------------------------------------------------
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DR EMBL; L11285; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC000471; AAH00471.1; -; mRNA.
DR EMBL; BC018645; AAH18645.1; -; mRNA.
DR PIR; A46723; A46723.
DR RefSeq; NP_109587.1; NM_030662.3.
DR UniGene; Hs.465627; -.
DR PDB; 1S9I; X-ray; 3.20 A; A/B=55-400.
DR PDB; 4H3Q; X-ray; 2.20 A; B=4-16.
DR PDBsum; 1S9I; -.
DR PDBsum; 4H3Q; -.
DR ProteinModelPortal; P36507; -.
DR SMR; P36507; 60-393.
DR DIP; DIP-29119N; -.
DR IntAct; P36507; 14.
DR MINT; MINT-99667; -.
DR STRING; 9606.ENSP00000262948; -.
DR BindingDB; P36507; -.
DR ChEMBL; CHEMBL2964; -.
DR GuidetoPHARMACOLOGY; 2063; -.
DR PhosphoSite; P36507; -.
DR DMDM; 547915; -.
DR REPRODUCTION-2DPAGE; IPI00003783; -.
DR PaxDb; P36507; -.
DR PeptideAtlas; P36507; -.
DR PRIDE; P36507; -.
DR DNASU; 5605; -.
DR Ensembl; ENST00000262948; ENSP00000262948; ENSG00000126934.
DR GeneID; 5605; -.
DR KEGG; hsa:5605; -.
DR UCSC; uc002lzj.3; human.
DR CTD; 5605; -.
DR GeneCards; GC19M004090; -.
DR H-InvDB; HIX0033655; -.
DR HGNC; HGNC:6842; MAP2K2.
DR HPA; CAB003835; -.
DR MIM; 601263; gene.
DR MIM; 615280; phenotype.
DR neXtProt; NX_P36507; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR PharmGKB; PA30587; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000234206; -.
DR HOVERGEN; HBG108518; -.
DR InParanoid; P36507; -.
DR KO; K04369; -.
DR OMA; RLKQPST; -.
DR OrthoDB; EOG7HF1KZ; -.
DR PhylomeDB; P36507; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P36507; -.
DR ChiTaRS; MAP2K2; human.
DR EvolutionaryTrace; P36507; -.
DR GeneWiki; MAP2K2; -.
DR GenomeRNAi; 5605; -.
DR NextBio; 21780; -.
DR PMAP-CutDB; P36507; -.
DR PRO; PR:P36507; -.
DR ArrayExpress; P36507; -.
DR Bgee; P36507; -.
DR CleanEx; HS_MAP2K2; -.
DR Genevestigator; P36507; -.
DR GO; GO:0005938; C:cell cortex; IEA:Ensembl.
DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0005769; C:early endosome; TAS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; TAS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; TAS:UniProtKB.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; NAS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:2000147; P:positive regulation of cell motility; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB.
DR GO; GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB.
DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Cardiomyopathy;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Ectodermal dysplasia; Kinase; Mental retardation; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1 400 Dual specificity mitogen-activated
FT protein kinase kinase 2.
FT /FTId=PRO_0000086372.
FT DOMAIN 72 369 Protein kinase.
FT NP_BIND 78 86 ATP (By similarity).
FT COMPBIAS 266 315 Pro-rich.
FT ACT_SITE 194 194 Proton acceptor (By similarity).
FT BINDING 101 101 ATP (By similarity).
FT SITE 10 11 Cleavage; by anthrax lethal factor.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 222 222 O-acetylserine; by Yersinia yopJ;
FT alternate.
FT MOD_RES 222 222 Phosphoserine; by RAF; alternate.
FT MOD_RES 226 226 O-acetylserine; by Yersinia yopJ;
FT alternate.
FT MOD_RES 226 226 Phosphoserine; alternate.
FT MOD_RES 293 293 Phosphoserine.
FT MOD_RES 295 295 Phosphoserine.
FT MOD_RES 394 394 Phosphothreonine.
FT MOD_RES 396 396 Phosphothreonine.
FT VARIANT 57 57 F -> C (in CFC4).
FT /FTId=VAR_035095.
FT VARIANT 57 57 F -> V (in CFC4).
FT /FTId=VAR_069781.
FT VARIANT 128 128 P -> Q (in CFC4; results in increased
FT kinase activity).
FT /FTId=VAR_069782.
FT VARIANT 134 134 Y -> H (in CFC4).
FT /FTId=VAR_069783.
FT HELIX 69 71
FT STRAND 72 80
FT STRAND 85 91
FT TURN 92 94
FT STRAND 97 103
FT HELIX 110 119
FT HELIX 120 122
FT STRAND 133 148
FT HELIX 155 161
FT STRAND 162 164
FT HELIX 167 186
FT HELIX 197 199
FT STRAND 200 202
FT STRAND 208 210
FT HELIX 217 222
FT HELIX 236 239
FT HELIX 246 262
FT HELIX 272 279
FT HELIX 318 327
FT TURN 335 337
FT HELIX 340 349
FT TURN 354 356
FT HELIX 360 364
FT HELIX 367 374
FT HELIX 379 386
SQ SEQUENCE 400 AA; 44424 MW; 3401D522515C30A5 CRC64;
MLARRKPVLP ALTINPTIAE GPSPTSEGAS EANLVDLQKK LEELELDEQQ KKRLEAFLTQ
KAKVGELKDD DFERISELGA GNGGVVTKVQ HRPSGLIMAR KLIHLEIKPA IRNQIIRELQ
VLHECNSPYI VGFYGAFYSD GEISICMEHM DGGSLDQVLK EAKRIPEEIL GKVSIAVLRG
LAYLREKHQI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DSMANSFVGT RSYMAPERLQ
GTHYSVQSDI WSMGLSLVEL AVGRYPIPPP DAKELEAIFG RPVVDGEEGE PHSISPRPRP
PGRPVSGHGM DSRPAMAIFE LLDYIVNEPP PKLPNGVFTP DFQEFVNKCL IKNPAERADL
KMLTNHTFIK RSEVEEVDFA GWLCKTLRLN QPGTPTRTAV
//
MIM
601263
*RECORD*
*FIELD* NO
601263
*FIELD* TI
*601263 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; MAP2K2
;;PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 2; PRKMK2;;
read moreMKK2; MAPKK2;;
MAPK/ERK KINASE 2; MEK2
*FIELD* TX
CLONING
Zheng and Guan (1993) isolated and sequenced 2 human cDNAs encoding
members of the MAP kinase kinase (MAP2K) family, designated MEK1
(176872) and MEK2 by them. The MEK2 cDNA encodes a predicted 400-amino
acid protein that shares 80% sequence identity with human MEK1.
Brott et al. (1993) cloned the mouse Mek2 gene.
GENE FUNCTION
Zheng and Guan (1993) showed that recombinant MEK2 and MEK1 both could
activate human ERK1 (601795) in vitro. They further characterized
biochemically the 2 MAP2Ks.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the extracellular signal-regulated kinase ERK,
c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein
kinase (MAPK) pathways and inhibition of the nuclear factor kappa B
(NF-kappa-B; see 164011) pathway. The expression of YopJ has been
correlated with the induction of apoptosis by Yersinia. Using a yeast
2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA
library, Orth et al. (1999) identified mammalian binding partners of
YopJ. These included the fusion proteins of the GAL4 activation domain
with MAPK kinases MKK1 (176872), MKK2, and MKK4/SEK1 (601335). YopJ was
found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315),
MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both
phosphorylation and subsequent activation of the MKKs. These results
explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38,
and NF-kappa-B signaling pathways, preventing cytokine synthesis and
promoting apoptosis. YopJ-related proteins that are found in a number of
bacterial pathogens of animals and plants may function to block MKKs so
that host signaling responses can be modulated upon infection.
Mittal et al. (2006) found that the Yersinia YopJ virulence factor
inhibited the host inflammatory response and induced apoptosis of immune
cells by catalyzing acetylation of 2 ser residues in the activation loop
of MEK2, thereby blocking MEK2 activation and signal propagation. YopJ
also caused acetylation of a thr residue in the activation loop of both
IKKA (CHUK; 600664) and IKKB (IKBKB; 603258). Mittal et al. (2006)
concluded that ser/thr acetylation is a mode of action for bacterial
toxins that may also occur under nonpathogenic conditions to regulate
protein function.
Influenza A viruses are significant causes of morbidity and mortality
worldwide. Annually updated vaccines may prevent disease, and antivirals
are effective treatment early in disease when symptoms are often
nonspecific. Viral replication is supported by intracellular signaling
events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an
inhibitor of the RAF1 (164760)/MEK/ERK pathway (see Favata et al.
(1998)), Pleschka et al. (2001) examined the cellular response to
infection with influenza A. U0126 suppressed both the early and late ERK
activation phases after virus infection. Inhibition of the signaling
pathway occurred without impairing the synthesis of viral RNA or
protein, or the import of viral ribonucleoprotein complexes (RNP) into
the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the
export of viral RNP without affecting the cellular mRNA export pathway.
Pleschka et al. (2001) proposed that ERK regulates a cellular factor
involved in the viral nuclear export protein function. They suggested
that local application of MEK inhibitors may have only minor toxic
effects on the host while inhibiting viral replication without giving
rise to drug-resistant virus variants.
Scholl et al. (2007) found that conditional deletion of either Mek1 or
Mek2 in mouse skin had no effect on epidermal development, but combined
Mek1/Mek2 deletion during embryonic development or in adulthood
abolished Erk1/Erk2 (MAPK1; 176948) phosphorylation and led to
hypoproliferation, apoptosis, skin barrier defects, and death.
Conversely, a single copy of either allele was sufficient for normal
development. Combined Mek1/Mek2 loss also abolished Raf-induced
hyperproliferation. To examine the effect of combined MEK deletion on
human skin, Scholl et al. (2007) used small interfering RNA to delete
MEK1 and MEK2 expression in normal primary human keratinocytes and used
these cells to regenerate human epidermal tissue on human dermis, which
was grafted onto immune-deficient mice. Control keratinocytes or those
lacking either MEK1 or MEK2 were able to regenerate 6 days after
grafting. In contrast, combined depletion of MEK1 and MEK2 led to either
graft failure or markedly hypoplastic epidermis that nonetheless
contained an intact stratum corneum. ERK2 expression rescued the defect.
Scholl et al. (2007) concluded that MEK1 and MEK2 are functionally
redundant in the epidermis and function in a linear relay in the MAPK
pathway.
MAPPING
Brott et al. (1993) mapped the mouse Mek2 gene to chromosome 10.
Puttagunta et al., (2000) constructed a cosmid/BAC map of human
chromosome 19p13.3 and localized over 50 genes, including MAP2K2, to the
contig. The 19p13.3 region shows syntenic homology with mouse chromosome
10.
Meloche et al. (2000) had erroneously mapped the MAP2K2 gene to 7q32.
MOLECULAR GENETICS
- Cardiofaciocutaneous Syndrome
In 23 patients with cardiofaciocutaneous syndrome (CFC4; 615280),
Rodriguez-Viciana et al. (2006) searched for mutations in downstream
effectors of RAS and found a missense mutation in MEK2 in 1 patient
(F57C; 601263.0001). The F57 codon of MEK2 is equivalent to codon F53 of
MEK1, which was mutated in another CFC patient (176872.0001).
In 3 (5.9%) of 51 CFC patients, Schulz et al. (2008) identified 2
different mutations in the MAP2K2 gene (F57V; 601263.0002 and Y134H;
601263.0003).
Rauen et al. (2010) and Linden and Price (2011) independently reported 2
unrelated families with autosomal dominant transmission of CFC due to
heterozygous mutations in the MAP2K2 gene (P128Q, 601263.0004 and G132D,
601263.0005, respectively).
- Somatic Mutations
Nikolaev et al. (2012) performed exome sequencing to detect somatic
mutations in protein-coding regions in 7 melanoma cell lines and
donor-matched germline cells. All melanoma samples had high numbers of
somatic mutations, which showed the hallmark of UV-induced DNA repair.
Such a hallmark was absent in tumor sample-specific mutations in 2
metastases derived from the same individual. Two melanomas with
noncanonical BRAF mutations harbored gain-of-function MAP2K1 (MEK1;
176872) and MAP2K2 mutations, resulting in constitutive ERK
phosphorylation and higher resistance to MEK inhibitors. Screening a
larger cohort of individuals with melanoma revealed the presence of
recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an
overall frequency of 8%.
ANIMAL MODEL
Belanger et al. (2003) developed Mek2-deficient mice. Mutant mice were
viable and fertile and showed no phenotypic abnormalities. Mutant
embryonic fibroblasts and purified lymphocytes proliferated normally,
demonstrating that Mek2 is not required for reentry into the cell cycle
or for T-cell development. Belanger et al. (2003) concluded that MEK1
can compensate for a lack of MEK2 function.
*FIELD* AV
.0001
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PHE57CYS
In a patient with cardiofaciocutaneous syndrome (CFC4; 615280),
Rodriguez-Viciana et al. (2006) identified a T-to-G transversion at
nucleotide 170 of the MEK2 gene, resulting in a
phenylalanine-to-cysteine substitution at codon 57 (F57C).
By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S
(176872.0001) and Y130C (176872.0002) and the MEK2 mutant F57C could not
induce ERK signaling unless phosphorylated by RAF at 2 homologous serine
residues in the regulatory loop. When these serine residues were
replaced with alanines, ERK phosphorylation was significantly reduced in
the presence of RAF. However, the F57C MEK2 mutant was less dependent on
RAF signaling than the other mutants. This difference resulted in F57C
MEK2 being resistant to the selective RAF inhibitor SB-590885. However,
all 3 mutants were sensitive to the MEK inhibitor U0126. Senawong et al.
(2008) suggested that MEK inhibition could have potential therapeutic
value in CFC.
.0002
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PHE57VAL
In 2 patients with cardiofaciocutaneous syndrome (CFC4; 615280), Schulz
et al. (2008) identified a heterozygous de novo 169T-G transversion in
exon 2 of the MAP2K2 gene, resulting in a phe57-to-val (F57V)
substitution. This same codon is affected in F57C (601263.0001). Both
patients had a unique facial phenotype with a long narrow face, tall
forehead, low-set ears, severe ptosis, epicanthal folds, and prominent
supraorbital ridges.
.0003
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, TYR134HIS
In a patient with CFC (CFC4; 615280), Schulz et al. (2008) identified a
heterozygous 400T-C transition in exon 3 of the MAP2K2 gene, resulting
in a tyr134-to-his (Y134H) substitution.
.0004
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PRO128GLN
In affected members of a 4-generation Caucasian Cajun family with CFC
(CFC4; 615280), Rauen et al. (2010) identified a heterozygous 383C-A
transversion in exon 3 of the MAP2K2 gene, resulting in a pro128-to-gln
(P128Q) substitution. In vitro functional expression studies showed that
the mutant protein had increased kinase activity, but not as much as
other CFC-associated MAP2K2 mutations (e.g., F57C; 601263.0001), and was
considered a weak hypermorphic mutation. This was the first reported
case of vertical transmission of a MAP2K2 mutation in CFC. The phenotype
was variable, and included the classic craniofacial features, pulmonic
stenosis, ectodermal abnormalities, and variable degrees of learning
delays and disabilities. One of the mutation carriers died of acute
lymphocytic leukemia (ALL) at age 41 years, which the authors postulated
may have resulted from increased activity of the RAS pathway.
.0005
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, GLY132ASP
In a mother and her 2 sons with CFC4 (615280), Linden and Price (2011)
identified a heterozygous 395G-A transition in exon 3 of the MAP2K2
gene, resulting in a gly132-to-asp (G132D) substitution in a conserved
residue. The proband was a 46-year-old man with mildly delayed
development, pulmonary stenosis as a child, myopia, short stature,
tightly curled short hair, absent eyebrows, hyperelastic skin, and
multiple lentigines. His 40-year-old brother and 68-year-old mother had
similar features. Linden and Price (2011) emphasized the rarity of
autosomal dominant transmission of CFC, and noted that the mild
cognitive phenotype in these patients suggests greater reproductive
success.
*FIELD* RF
1. Belanger, L.-F.; Roy, S.; Tremblay, M.; Brott, B.; Steff, A.-M.;
Mourad, W.; Hugo, P.; Erikson, R.; Charron, J.: Mek2 is dispensable
for mouse growth and development. Molec. Cell. Biol. 23: 4778-4787,
2003.
2. Brott, B. K.; Alessandrini, A.; Largaespada, D. A.; Copeland, N.
G.; Jenkins, N. A.; Crews, C. M.; Erikson, R. L.: MEK2 is a kinase
related to MEK1 and is differentially expressed in murine tissues. Cell
Growth Differ. 4: 921-929, 1993.
3. Favata, M. F.; Horiuchi, K. Y.; Manos, E. J.; Daulerio, A. J.;
Stradley, D. A.; Feeser, W. S.; Van Dyk, D. E.; Pitts, W. J.; Earl,
R. A.; Hobbs, F.; Copeland, R. A.; Magolda, R. L.; Scherle, P. A.;
Trzaskos, J. M.: Identification of a novel inhibitor of mitogen-activated
protein kinase kinase. J. Biol. Chem. 273: 18623-18632, 1998.
4. Linden, H. C.; Price, S. M.: Cardiofaciocutaneous syndrome in
a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20:
86-88, 2011.
5. Meloche, S.; Gopalbhai, K.; Beatty, B. G.; Scherer, S. W.; Pellerin,
J.: Chromosome mapping of the human genes encoding the MAP kinase
kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet.
Cell Genet. 88: 249-252, 2000.
6. Mittal, R.; Peak-Chew, S.-Y.; McMahon, H. T.: Acetylation of MEK2
and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits
signaling. Proc. Nat. Acad. Sci. 18574-18579, 2006.
7. Nikolaev, S. I.; Rimoldi, D.; Iseli, C.; Valsesia, A.; Robyr, D.;
Gehrig, C.; Harshman, K.; Guipponi, M.; Bukach, O.; Zoete, V.; Michielin,
O.; Muehlethaler, K.; Speiser, D.; Beckmann, J. S.; Xenarios, I.;
Halazonetis, T. D.; Jongeneel, C. V.; Stevenson, B. J.; Antonarakis,
S. E.: Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2
mutations in melanoma. Nature Genet. 44: 133-139, 2012.
8. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
9. Pleschka, S.; Wolff, T.; Ehrhardt, C.; Hobom, G.; Planz, O.; Rapp,
U. R.; Ludwig, S.: Influenza virus propagation is impaired by inhibition
of the Raf/MEK/ERK signalling cascade. Nature Cell Biol. 3: 301-305,
2001.
10. Puttagunta, P.; Gordon, L. A.; Meyer, G. E.; Kapfhamer, D.; Lamerdin,
J. E.; Kantheti, P.; Portman, K. M.; Chung, W. K.; Jenne, D. E.; Olsen,
A. S.; Burmeister, M.: Comparative maps of human 19p13.3 and mouse
chromosome 10 allow identification of sequences at evolutionary breakpoints. Genome
Res. 10: 1369-1380, 2000.
11. Rauen, K. A.; Tidyman, W. E.; Estep, A. L.; Sampath, S.; Peltier,
H. M.; Bale, S. J.; Lacassie, Y.: Molecular and functional analysis
of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission
through four generations. Am. J. Med. Genet. 152A: 807-814, 2010.
12. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.
13. Scholl, F. A.; Dumesic, P. A.; Barragan, D. I.; Harada, K.; Bissonauth,
V.; Charron, J.; Khavari, P. A.: Mek1/2 MAPK kinases are essential
for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev.
Cell 12: 615-629, 2007.
14. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.
15. Senawong, T.; Phuchareon, J.; Ohara, O.; McCormick, F.; Rauen,
K. A.; Tetsu, O.: Germline mutations of MEK in cardio-facio-cutaneous
syndrome are sensitive to MEK and RAF inhibition: implications for
therapeutic options. Hum. Molec. Genet. 17: 419-430, 2008.
16. Zheng, C. F.; Guan, K. L.: Cloning and characterization of two
distinct human extracellular signal-regulated kinase activator kinases,
MEK1 and MEK2. J. Biol. Chem. 268: 11435-11439, 1993.
*FIELD* CN
Ada Hamosh - updated: 2/1/2013
Cassandra L. Kniffin - updated: 4/28/2011
Cassandra L. Kniffin - updated: 11/11/2010
Cassandra L. Kniffin - updated: 1/11/2010
Joanna S. Amberger - updated: 7/17/2009
Cassandra L. Kniffin - updated: 3/17/2008
Patricia A. Hartz - updated: 5/4/2007
Paul J. Converse - updated: 5/1/2007
Ada Hamosh - updated: 4/19/2006
Patricia A. Hartz - updated: 10/23/2003
Joanna S. Amberger - updated: 3/6/2001
Paul J. Converse - updated: 3/2/2001
Ada Hamosh - updated: 9/15/1999
*FIELD* CD
Mark H. Paalman: 5/16/1996
*FIELD* ED
alopez: 06/20/2013
alopez: 2/6/2013
terry: 2/1/2013
wwang: 5/10/2011
ckniffin: 4/28/2011
wwang: 11/15/2010
ckniffin: 11/11/2010
wwang: 1/22/2010
terry: 1/20/2010
ckniffin: 1/11/2010
carol: 7/17/2009
joanna: 7/17/2009
wwang: 3/19/2008
ckniffin: 3/17/2008
mgross: 5/23/2007
terry: 5/4/2007
mgross: 5/1/2007
alopez: 4/20/2006
terry: 4/19/2006
mgross: 10/23/2003
alopez: 7/11/2002
terry: 3/7/2001
joanna: 3/6/2001
mgross: 3/2/2001
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
psherman: 4/21/1998
psherman: 3/17/1998
mark: 5/20/1996
terry: 5/17/1996
mark: 5/16/1996
*RECORD*
*FIELD* NO
601263
*FIELD* TI
*601263 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; MAP2K2
;;PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 2; PRKMK2;;
read moreMKK2; MAPKK2;;
MAPK/ERK KINASE 2; MEK2
*FIELD* TX
CLONING
Zheng and Guan (1993) isolated and sequenced 2 human cDNAs encoding
members of the MAP kinase kinase (MAP2K) family, designated MEK1
(176872) and MEK2 by them. The MEK2 cDNA encodes a predicted 400-amino
acid protein that shares 80% sequence identity with human MEK1.
Brott et al. (1993) cloned the mouse Mek2 gene.
GENE FUNCTION
Zheng and Guan (1993) showed that recombinant MEK2 and MEK1 both could
activate human ERK1 (601795) in vitro. They further characterized
biochemically the 2 MAP2Ks.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the extracellular signal-regulated kinase ERK,
c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein
kinase (MAPK) pathways and inhibition of the nuclear factor kappa B
(NF-kappa-B; see 164011) pathway. The expression of YopJ has been
correlated with the induction of apoptosis by Yersinia. Using a yeast
2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA
library, Orth et al. (1999) identified mammalian binding partners of
YopJ. These included the fusion proteins of the GAL4 activation domain
with MAPK kinases MKK1 (176872), MKK2, and MKK4/SEK1 (601335). YopJ was
found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315),
MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both
phosphorylation and subsequent activation of the MKKs. These results
explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38,
and NF-kappa-B signaling pathways, preventing cytokine synthesis and
promoting apoptosis. YopJ-related proteins that are found in a number of
bacterial pathogens of animals and plants may function to block MKKs so
that host signaling responses can be modulated upon infection.
Mittal et al. (2006) found that the Yersinia YopJ virulence factor
inhibited the host inflammatory response and induced apoptosis of immune
cells by catalyzing acetylation of 2 ser residues in the activation loop
of MEK2, thereby blocking MEK2 activation and signal propagation. YopJ
also caused acetylation of a thr residue in the activation loop of both
IKKA (CHUK; 600664) and IKKB (IKBKB; 603258). Mittal et al. (2006)
concluded that ser/thr acetylation is a mode of action for bacterial
toxins that may also occur under nonpathogenic conditions to regulate
protein function.
Influenza A viruses are significant causes of morbidity and mortality
worldwide. Annually updated vaccines may prevent disease, and antivirals
are effective treatment early in disease when symptoms are often
nonspecific. Viral replication is supported by intracellular signaling
events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an
inhibitor of the RAF1 (164760)/MEK/ERK pathway (see Favata et al.
(1998)), Pleschka et al. (2001) examined the cellular response to
infection with influenza A. U0126 suppressed both the early and late ERK
activation phases after virus infection. Inhibition of the signaling
pathway occurred without impairing the synthesis of viral RNA or
protein, or the import of viral ribonucleoprotein complexes (RNP) into
the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the
export of viral RNP without affecting the cellular mRNA export pathway.
Pleschka et al. (2001) proposed that ERK regulates a cellular factor
involved in the viral nuclear export protein function. They suggested
that local application of MEK inhibitors may have only minor toxic
effects on the host while inhibiting viral replication without giving
rise to drug-resistant virus variants.
Scholl et al. (2007) found that conditional deletion of either Mek1 or
Mek2 in mouse skin had no effect on epidermal development, but combined
Mek1/Mek2 deletion during embryonic development or in adulthood
abolished Erk1/Erk2 (MAPK1; 176948) phosphorylation and led to
hypoproliferation, apoptosis, skin barrier defects, and death.
Conversely, a single copy of either allele was sufficient for normal
development. Combined Mek1/Mek2 loss also abolished Raf-induced
hyperproliferation. To examine the effect of combined MEK deletion on
human skin, Scholl et al. (2007) used small interfering RNA to delete
MEK1 and MEK2 expression in normal primary human keratinocytes and used
these cells to regenerate human epidermal tissue on human dermis, which
was grafted onto immune-deficient mice. Control keratinocytes or those
lacking either MEK1 or MEK2 were able to regenerate 6 days after
grafting. In contrast, combined depletion of MEK1 and MEK2 led to either
graft failure or markedly hypoplastic epidermis that nonetheless
contained an intact stratum corneum. ERK2 expression rescued the defect.
Scholl et al. (2007) concluded that MEK1 and MEK2 are functionally
redundant in the epidermis and function in a linear relay in the MAPK
pathway.
MAPPING
Brott et al. (1993) mapped the mouse Mek2 gene to chromosome 10.
Puttagunta et al., (2000) constructed a cosmid/BAC map of human
chromosome 19p13.3 and localized over 50 genes, including MAP2K2, to the
contig. The 19p13.3 region shows syntenic homology with mouse chromosome
10.
Meloche et al. (2000) had erroneously mapped the MAP2K2 gene to 7q32.
MOLECULAR GENETICS
- Cardiofaciocutaneous Syndrome
In 23 patients with cardiofaciocutaneous syndrome (CFC4; 615280),
Rodriguez-Viciana et al. (2006) searched for mutations in downstream
effectors of RAS and found a missense mutation in MEK2 in 1 patient
(F57C; 601263.0001). The F57 codon of MEK2 is equivalent to codon F53 of
MEK1, which was mutated in another CFC patient (176872.0001).
In 3 (5.9%) of 51 CFC patients, Schulz et al. (2008) identified 2
different mutations in the MAP2K2 gene (F57V; 601263.0002 and Y134H;
601263.0003).
Rauen et al. (2010) and Linden and Price (2011) independently reported 2
unrelated families with autosomal dominant transmission of CFC due to
heterozygous mutations in the MAP2K2 gene (P128Q, 601263.0004 and G132D,
601263.0005, respectively).
- Somatic Mutations
Nikolaev et al. (2012) performed exome sequencing to detect somatic
mutations in protein-coding regions in 7 melanoma cell lines and
donor-matched germline cells. All melanoma samples had high numbers of
somatic mutations, which showed the hallmark of UV-induced DNA repair.
Such a hallmark was absent in tumor sample-specific mutations in 2
metastases derived from the same individual. Two melanomas with
noncanonical BRAF mutations harbored gain-of-function MAP2K1 (MEK1;
176872) and MAP2K2 mutations, resulting in constitutive ERK
phosphorylation and higher resistance to MEK inhibitors. Screening a
larger cohort of individuals with melanoma revealed the presence of
recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an
overall frequency of 8%.
ANIMAL MODEL
Belanger et al. (2003) developed Mek2-deficient mice. Mutant mice were
viable and fertile and showed no phenotypic abnormalities. Mutant
embryonic fibroblasts and purified lymphocytes proliferated normally,
demonstrating that Mek2 is not required for reentry into the cell cycle
or for T-cell development. Belanger et al. (2003) concluded that MEK1
can compensate for a lack of MEK2 function.
*FIELD* AV
.0001
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PHE57CYS
In a patient with cardiofaciocutaneous syndrome (CFC4; 615280),
Rodriguez-Viciana et al. (2006) identified a T-to-G transversion at
nucleotide 170 of the MEK2 gene, resulting in a
phenylalanine-to-cysteine substitution at codon 57 (F57C).
By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S
(176872.0001) and Y130C (176872.0002) and the MEK2 mutant F57C could not
induce ERK signaling unless phosphorylated by RAF at 2 homologous serine
residues in the regulatory loop. When these serine residues were
replaced with alanines, ERK phosphorylation was significantly reduced in
the presence of RAF. However, the F57C MEK2 mutant was less dependent on
RAF signaling than the other mutants. This difference resulted in F57C
MEK2 being resistant to the selective RAF inhibitor SB-590885. However,
all 3 mutants were sensitive to the MEK inhibitor U0126. Senawong et al.
(2008) suggested that MEK inhibition could have potential therapeutic
value in CFC.
.0002
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PHE57VAL
In 2 patients with cardiofaciocutaneous syndrome (CFC4; 615280), Schulz
et al. (2008) identified a heterozygous de novo 169T-G transversion in
exon 2 of the MAP2K2 gene, resulting in a phe57-to-val (F57V)
substitution. This same codon is affected in F57C (601263.0001). Both
patients had a unique facial phenotype with a long narrow face, tall
forehead, low-set ears, severe ptosis, epicanthal folds, and prominent
supraorbital ridges.
.0003
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, TYR134HIS
In a patient with CFC (CFC4; 615280), Schulz et al. (2008) identified a
heterozygous 400T-C transition in exon 3 of the MAP2K2 gene, resulting
in a tyr134-to-his (Y134H) substitution.
.0004
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, PRO128GLN
In affected members of a 4-generation Caucasian Cajun family with CFC
(CFC4; 615280), Rauen et al. (2010) identified a heterozygous 383C-A
transversion in exon 3 of the MAP2K2 gene, resulting in a pro128-to-gln
(P128Q) substitution. In vitro functional expression studies showed that
the mutant protein had increased kinase activity, but not as much as
other CFC-associated MAP2K2 mutations (e.g., F57C; 601263.0001), and was
considered a weak hypermorphic mutation. This was the first reported
case of vertical transmission of a MAP2K2 mutation in CFC. The phenotype
was variable, and included the classic craniofacial features, pulmonic
stenosis, ectodermal abnormalities, and variable degrees of learning
delays and disabilities. One of the mutation carriers died of acute
lymphocytic leukemia (ALL) at age 41 years, which the authors postulated
may have resulted from increased activity of the RAS pathway.
.0005
CARDIOFACIOCUTANEOUS SYNDROME 4
MAP2K2, GLY132ASP
In a mother and her 2 sons with CFC4 (615280), Linden and Price (2011)
identified a heterozygous 395G-A transition in exon 3 of the MAP2K2
gene, resulting in a gly132-to-asp (G132D) substitution in a conserved
residue. The proband was a 46-year-old man with mildly delayed
development, pulmonary stenosis as a child, myopia, short stature,
tightly curled short hair, absent eyebrows, hyperelastic skin, and
multiple lentigines. His 40-year-old brother and 68-year-old mother had
similar features. Linden and Price (2011) emphasized the rarity of
autosomal dominant transmission of CFC, and noted that the mild
cognitive phenotype in these patients suggests greater reproductive
success.
*FIELD* RF
1. Belanger, L.-F.; Roy, S.; Tremblay, M.; Brott, B.; Steff, A.-M.;
Mourad, W.; Hugo, P.; Erikson, R.; Charron, J.: Mek2 is dispensable
for mouse growth and development. Molec. Cell. Biol. 23: 4778-4787,
2003.
2. Brott, B. K.; Alessandrini, A.; Largaespada, D. A.; Copeland, N.
G.; Jenkins, N. A.; Crews, C. M.; Erikson, R. L.: MEK2 is a kinase
related to MEK1 and is differentially expressed in murine tissues. Cell
Growth Differ. 4: 921-929, 1993.
3. Favata, M. F.; Horiuchi, K. Y.; Manos, E. J.; Daulerio, A. J.;
Stradley, D. A.; Feeser, W. S.; Van Dyk, D. E.; Pitts, W. J.; Earl,
R. A.; Hobbs, F.; Copeland, R. A.; Magolda, R. L.; Scherle, P. A.;
Trzaskos, J. M.: Identification of a novel inhibitor of mitogen-activated
protein kinase kinase. J. Biol. Chem. 273: 18623-18632, 1998.
4. Linden, H. C.; Price, S. M.: Cardiofaciocutaneous syndrome in
a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20:
86-88, 2011.
5. Meloche, S.; Gopalbhai, K.; Beatty, B. G.; Scherer, S. W.; Pellerin,
J.: Chromosome mapping of the human genes encoding the MAP kinase
kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet.
Cell Genet. 88: 249-252, 2000.
6. Mittal, R.; Peak-Chew, S.-Y.; McMahon, H. T.: Acetylation of MEK2
and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits
signaling. Proc. Nat. Acad. Sci. 18574-18579, 2006.
7. Nikolaev, S. I.; Rimoldi, D.; Iseli, C.; Valsesia, A.; Robyr, D.;
Gehrig, C.; Harshman, K.; Guipponi, M.; Bukach, O.; Zoete, V.; Michielin,
O.; Muehlethaler, K.; Speiser, D.; Beckmann, J. S.; Xenarios, I.;
Halazonetis, T. D.; Jongeneel, C. V.; Stevenson, B. J.; Antonarakis,
S. E.: Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2
mutations in melanoma. Nature Genet. 44: 133-139, 2012.
8. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
9. Pleschka, S.; Wolff, T.; Ehrhardt, C.; Hobom, G.; Planz, O.; Rapp,
U. R.; Ludwig, S.: Influenza virus propagation is impaired by inhibition
of the Raf/MEK/ERK signalling cascade. Nature Cell Biol. 3: 301-305,
2001.
10. Puttagunta, P.; Gordon, L. A.; Meyer, G. E.; Kapfhamer, D.; Lamerdin,
J. E.; Kantheti, P.; Portman, K. M.; Chung, W. K.; Jenne, D. E.; Olsen,
A. S.; Burmeister, M.: Comparative maps of human 19p13.3 and mouse
chromosome 10 allow identification of sequences at evolutionary breakpoints. Genome
Res. 10: 1369-1380, 2000.
11. Rauen, K. A.; Tidyman, W. E.; Estep, A. L.; Sampath, S.; Peltier,
H. M.; Bale, S. J.; Lacassie, Y.: Molecular and functional analysis
of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission
through four generations. Am. J. Med. Genet. 152A: 807-814, 2010.
12. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.
13. Scholl, F. A.; Dumesic, P. A.; Barragan, D. I.; Harada, K.; Bissonauth,
V.; Charron, J.; Khavari, P. A.: Mek1/2 MAPK kinases are essential
for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev.
Cell 12: 615-629, 2007.
14. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.
15. Senawong, T.; Phuchareon, J.; Ohara, O.; McCormick, F.; Rauen,
K. A.; Tetsu, O.: Germline mutations of MEK in cardio-facio-cutaneous
syndrome are sensitive to MEK and RAF inhibition: implications for
therapeutic options. Hum. Molec. Genet. 17: 419-430, 2008.
16. Zheng, C. F.; Guan, K. L.: Cloning and characterization of two
distinct human extracellular signal-regulated kinase activator kinases,
MEK1 and MEK2. J. Biol. Chem. 268: 11435-11439, 1993.
*FIELD* CN
Ada Hamosh - updated: 2/1/2013
Cassandra L. Kniffin - updated: 4/28/2011
Cassandra L. Kniffin - updated: 11/11/2010
Cassandra L. Kniffin - updated: 1/11/2010
Joanna S. Amberger - updated: 7/17/2009
Cassandra L. Kniffin - updated: 3/17/2008
Patricia A. Hartz - updated: 5/4/2007
Paul J. Converse - updated: 5/1/2007
Ada Hamosh - updated: 4/19/2006
Patricia A. Hartz - updated: 10/23/2003
Joanna S. Amberger - updated: 3/6/2001
Paul J. Converse - updated: 3/2/2001
Ada Hamosh - updated: 9/15/1999
*FIELD* CD
Mark H. Paalman: 5/16/1996
*FIELD* ED
alopez: 06/20/2013
alopez: 2/6/2013
terry: 2/1/2013
wwang: 5/10/2011
ckniffin: 4/28/2011
wwang: 11/15/2010
ckniffin: 11/11/2010
wwang: 1/22/2010
terry: 1/20/2010
ckniffin: 1/11/2010
carol: 7/17/2009
joanna: 7/17/2009
wwang: 3/19/2008
ckniffin: 3/17/2008
mgross: 5/23/2007
terry: 5/4/2007
mgross: 5/1/2007
alopez: 4/20/2006
terry: 4/19/2006
mgross: 10/23/2003
alopez: 7/11/2002
terry: 3/7/2001
joanna: 3/6/2001
mgross: 3/2/2001
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
psherman: 4/21/1998
psherman: 3/17/1998
mark: 5/20/1996
terry: 5/17/1996
mark: 5/16/1996
MIM
615280
*RECORD*
*FIELD* NO
615280
*FIELD* TI
#615280 CARDIOFACIOCUTANEOUS SYNDROME 4; CFC4
*FIELD* TX
A number sign (#) is used with this entry because this form of
read morecardiofaciocutaneous syndrome (CFC4) is caused by heterozygous mutation
in the MAPK2K2 gene (601263) on chromosome 19p13.3.
For a general phenotypic description and a discussion of genetic
heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).
DESCRIPTION
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly
disorder in which individuals have characteristic craniofacial features,
cardiac defects, ectodermal anomalies, gastrointestinal dysfunction, and
neurocognitive delay (summary by Rauen et al., 2010).
CLINICAL FEATURES
Rodriguez-Viciana et al. (2006) identified 1 patient with CFC4 among 23
CFC patients. The child had characteristic craniofacial features,
ectodermal abnormalities, aortic valve defect and nonprogressive
ventricular septal hypertrophy, short stature with growth hormone
deficiency, scoliosis and pectus deformity, ocular abnormalities
(nystagmus, strabismus, myopia, bilateral cataracts and optic nerve
hypoplasia), cerebellar hypoplasia, prominence of the lateral
ventricles, thinning of the corpus callosum, and moderate developmental
delay. Hypotonia, heat intolerance, and excessive sweating were also
present.
Rauen et al. (2010) reported the first documented case of vertical
transmission of CFC in a 4-generation Caucasian Cajun family. The
proband was initially evaluated at age 7.5 months for short stature and
mild pulmonic stenosis. He was found to have mildly delayed motor
milestones and classic facial features of the disorder, including high
forehead with bitemporal narrowing and telecanthus, as well as
ectodermal anomalies. The mother had similar facial features and mild
pulmonic stenosis, and several family members reportedly had similar
facial and ectodermal features, as well as learning delays and
disabilities. After another affected boy was born to this mother,
molecular genetic testing was undertaken and the mutation in MEK2
identified. Two individuals with mutations in this pedigree developed
cancer: the proband's maternal great grandmother developed a large
B-cell lymphoma at age 70 and the proband's maternal great uncle died of
acute lymphoblastic leukemia (ALL) at age 41 years.
Linden and Price (2011) reported the second family showing vertical
transmission of CFC4. The proband was a 46-year-old man with mildly
delayed development, pulmonary stenosis as a child, myopia, short
stature, tightly curled short hair, absent eyebrows, hyperelastic skin,
and multiple lentigines. His 40-year-old brother and 68-year-old mother
had similar features. Linden and Price (2011) emphasized the mild
cognitive phenotype in these patients, suggesting greater reproductive
success.
MOLECULAR GENETICS
Cardiofaciocutaneous syndrome most commonly occurs as a sporadic
disorder, resulting from de novo heterozygous mutations in any of the 4
genes associated with the disorder. Rauen et al. (2010) reported the
first documented case of vertical transmission of CFC in a 4-generation
Caucasian Cajun family. After another affected boy was born to this
mother, molecular genetic testing was undertaken, and a heterozygous
mutation in the MEK2 gene (P128Q; 601263.0004) was found. One of the
mutation carriers died of acute lymphocytic leukemia (ALL) at age 41
years, which Rauen et al. (2010) postulated may have resulted from
increased activity of the RAS pathway.
Linden and Price (2011) reported another family with autosomal dominant
transmission of CFC associated with a heterozygous mutation in the MEK2
gene (G132D; 601263.0005).
In 5 of 23 CFC patients screened for BRAF (164757) mutations (22%),
Rodriguez-Viciana et al. (2006) identified no BRAF mutation. Three of
these individuals had missense mutations in MEK1 (176872) or MEK2
(601263), which encode downstream effectors of BRAF. Two individuals had
missense mutations in MEK1 and 1 had a missense mutation in MEK2. One
mutation in MEK1 was a phe53-to-ser substitution (F53S; 176872.0001);
phe53 is the equivalent position to the codon changed in the MEK2
mutation, phe57 to cys (F57C; 601263.0001). Rodriguez-Viciana et al.
(2006) suggested that substitutions of this residue may have similar
functional consequences in the 2 family isoforms. All 3 MEK mutations
were found to be more active than wildtype MEK in stimulating ERK
phosphorylation.
Schulz et al. (2008) identified 2 different missense mutations in MEK2
in 3 unrelated patients with CFC. Among 51 patients with CFC, Schulz et
al. (2008) identified mutations in the BRAF (47%), MAP2K1 (9.8%), MAP2K2
(5.9%), and KRAS (190070) (5.9%) genes. Careful assessment of facial
features suggested that patients with MAP2K1 mutations showed
macrostomia and horizontal shape of the palpebral fissures, whereas
those with MAP2K2 mutations had a long, narrow face with a high
forehead, low-set ears, severe ptosis, epicanthal folds, and prominent
supraorbital ridges.
*FIELD* RF
1. Linden, H. C.; Price, S. M.: Cardiofaciocutaneous syndrome in
a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20:
86-88, 2011.
2. Rauen, K. A.; Tidyman, W. E.; Estep, A. L.; Sampath, S.; Peltier,
H. M.; Bale, S. J.; Lacassie, Y.: Molecular and functional analysis
of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission
through four generations. Am. J. Med. Genet. 152A: 807-814, 2010.
3. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.
4. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.
*FIELD* CD
Anne M. Stumpf: 6/17/2013
*FIELD* ED
alopez: 06/21/2013
alopez: 6/20/2013
*RECORD*
*FIELD* NO
615280
*FIELD* TI
#615280 CARDIOFACIOCUTANEOUS SYNDROME 4; CFC4
*FIELD* TX
A number sign (#) is used with this entry because this form of
read morecardiofaciocutaneous syndrome (CFC4) is caused by heterozygous mutation
in the MAPK2K2 gene (601263) on chromosome 19p13.3.
For a general phenotypic description and a discussion of genetic
heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).
DESCRIPTION
Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly
disorder in which individuals have characteristic craniofacial features,
cardiac defects, ectodermal anomalies, gastrointestinal dysfunction, and
neurocognitive delay (summary by Rauen et al., 2010).
CLINICAL FEATURES
Rodriguez-Viciana et al. (2006) identified 1 patient with CFC4 among 23
CFC patients. The child had characteristic craniofacial features,
ectodermal abnormalities, aortic valve defect and nonprogressive
ventricular septal hypertrophy, short stature with growth hormone
deficiency, scoliosis and pectus deformity, ocular abnormalities
(nystagmus, strabismus, myopia, bilateral cataracts and optic nerve
hypoplasia), cerebellar hypoplasia, prominence of the lateral
ventricles, thinning of the corpus callosum, and moderate developmental
delay. Hypotonia, heat intolerance, and excessive sweating were also
present.
Rauen et al. (2010) reported the first documented case of vertical
transmission of CFC in a 4-generation Caucasian Cajun family. The
proband was initially evaluated at age 7.5 months for short stature and
mild pulmonic stenosis. He was found to have mildly delayed motor
milestones and classic facial features of the disorder, including high
forehead with bitemporal narrowing and telecanthus, as well as
ectodermal anomalies. The mother had similar facial features and mild
pulmonic stenosis, and several family members reportedly had similar
facial and ectodermal features, as well as learning delays and
disabilities. After another affected boy was born to this mother,
molecular genetic testing was undertaken and the mutation in MEK2
identified. Two individuals with mutations in this pedigree developed
cancer: the proband's maternal great grandmother developed a large
B-cell lymphoma at age 70 and the proband's maternal great uncle died of
acute lymphoblastic leukemia (ALL) at age 41 years.
Linden and Price (2011) reported the second family showing vertical
transmission of CFC4. The proband was a 46-year-old man with mildly
delayed development, pulmonary stenosis as a child, myopia, short
stature, tightly curled short hair, absent eyebrows, hyperelastic skin,
and multiple lentigines. His 40-year-old brother and 68-year-old mother
had similar features. Linden and Price (2011) emphasized the mild
cognitive phenotype in these patients, suggesting greater reproductive
success.
MOLECULAR GENETICS
Cardiofaciocutaneous syndrome most commonly occurs as a sporadic
disorder, resulting from de novo heterozygous mutations in any of the 4
genes associated with the disorder. Rauen et al. (2010) reported the
first documented case of vertical transmission of CFC in a 4-generation
Caucasian Cajun family. After another affected boy was born to this
mother, molecular genetic testing was undertaken, and a heterozygous
mutation in the MEK2 gene (P128Q; 601263.0004) was found. One of the
mutation carriers died of acute lymphocytic leukemia (ALL) at age 41
years, which Rauen et al. (2010) postulated may have resulted from
increased activity of the RAS pathway.
Linden and Price (2011) reported another family with autosomal dominant
transmission of CFC associated with a heterozygous mutation in the MEK2
gene (G132D; 601263.0005).
In 5 of 23 CFC patients screened for BRAF (164757) mutations (22%),
Rodriguez-Viciana et al. (2006) identified no BRAF mutation. Three of
these individuals had missense mutations in MEK1 (176872) or MEK2
(601263), which encode downstream effectors of BRAF. Two individuals had
missense mutations in MEK1 and 1 had a missense mutation in MEK2. One
mutation in MEK1 was a phe53-to-ser substitution (F53S; 176872.0001);
phe53 is the equivalent position to the codon changed in the MEK2
mutation, phe57 to cys (F57C; 601263.0001). Rodriguez-Viciana et al.
(2006) suggested that substitutions of this residue may have similar
functional consequences in the 2 family isoforms. All 3 MEK mutations
were found to be more active than wildtype MEK in stimulating ERK
phosphorylation.
Schulz et al. (2008) identified 2 different missense mutations in MEK2
in 3 unrelated patients with CFC. Among 51 patients with CFC, Schulz et
al. (2008) identified mutations in the BRAF (47%), MAP2K1 (9.8%), MAP2K2
(5.9%), and KRAS (190070) (5.9%) genes. Careful assessment of facial
features suggested that patients with MAP2K1 mutations showed
macrostomia and horizontal shape of the palpebral fissures, whereas
those with MAP2K2 mutations had a long, narrow face with a high
forehead, low-set ears, severe ptosis, epicanthal folds, and prominent
supraorbital ridges.
*FIELD* RF
1. Linden, H. C.; Price, S. M.: Cardiofaciocutaneous syndrome in
a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20:
86-88, 2011.
2. Rauen, K. A.; Tidyman, W. E.; Estep, A. L.; Sampath, S.; Peltier,
H. M.; Bale, S. J.; Lacassie, Y.: Molecular and functional analysis
of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission
through four generations. Am. J. Med. Genet. 152A: 807-814, 2010.
3. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.
4. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.
*FIELD* CD
Anne M. Stumpf: 6/17/2013
*FIELD* ED
alopez: 06/21/2013
alopez: 6/20/2013