Full text data of MAP3K1
MAP3K1
(MAPKKK1, MEKK, MEKK1)
[Confidence: low (only semi-automatic identification from reviews)]
Mitogen-activated protein kinase kinase kinase 1; 2.7.11.25 (MAPK/ERK kinase kinase 1; MEK kinase 1; MEKK 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Mitogen-activated protein kinase kinase kinase 1; 2.7.11.25 (MAPK/ERK kinase kinase 1; MEK kinase 1; MEKK 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13233
ID M3K1_HUMAN Reviewed; 1512 AA.
AC Q13233;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-DEC-2008, sequence version 4.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 1;
DE EC=2.7.11.25;
DE AltName: Full=MAPK/ERK kinase kinase 1;
DE Short=MEK kinase 1;
DE Short=MEKK 1;
GN Name=MAP3K1; Synonyms=MAPKKK1, MEKK, MEKK1;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-1512, FUNCTION, AND INTERACTION WITH
RP MAP2K4.
RX PubMed=9808624;
RA Xia Y., Wu Z., Su B., Murray B., Karin M.;
RT "JNKK1 organizes a MAP kinase module through specific and sequential
RT interactions with upstream and downstream components mediated by its
RT amino-terminal extension.";
RL Genes Dev. 12:3369-3381(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1238-1274.
RC TISSUE=Leukocyte;
RX PubMed=8597633; DOI=10.1007/BF00539003;
RA Vinik B.S., Kay E.S., Fiedorek F.T. Jr.;
RT "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and
RT human chromosome 5.";
RL Mamm. Genome 6:782-783(1995).
RN [4]
RP INTERACTION WITH AXIN1.
RX PubMed=12223491; DOI=10.1074/jbc.M208099200;
RA Rui H.L., Fan E., Zhou H.M., Xu Z., Zhang Y., Lin S.C.;
RT "SUMO-1 modification of the C-terminal KVEKVD of Axin is required for
RT JNK activation but has no effect on Wnt signaling.";
RL J. Biol. Chem. 277:42981-42986(2002).
RN [5]
RP INTERACTION WITH AXIN1.
RX PubMed=15262978; DOI=10.1074/jbc.M404598200;
RA Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C.;
RT "The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal
RT kinase activation by Axin and dishevelled through distinct
RT mechanisms.";
RL J. Biol. Chem. 279:39366-39373(2004).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-154 AND SER-1043, 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 [8]
RP INTERACTION WITH STK38.
RX PubMed=17906693; DOI=10.1038/sj.onc.1210828;
RA Enomoto A., Kido N., Ito M., Morita A., Matsumoto Y., Takamatsu N.,
RA Hosoi Y., Miyagawa K.;
RT "Negative regulation of MEKK1/2 signaling by serine-threonine kinase
RT 38 (STK38).";
RL Oncogene 27:1930-1938(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292; SER-297; SER-300;
RP SER-507 AND SER-1018, AND 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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275 AND SER-292, AND
RP MASS SPECTROMETRY.
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 [12]
RP VARIANTS [LARGE SCALE ANALYSIS] ASN-92 AND SER-443.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [13]
RP VARIANTS SRXY6 PRO-189; ARG-189; ILE-GLN-211 INS AND ARG-616, AND
RP CHARACTERIZATION OF VARIANTS SRXY6 PRO-189 AND ARG-189.
RX PubMed=21129722; DOI=10.1016/j.ajhg.2010.11.003;
RA Pearlman A., Loke J., Le Caignec C., White S., Chin L., Friedman A.,
RA Warr N., Willan J., Brauer D., Farmer C., Brooks E., Oddoux C.,
RA Riley B., Shajahan S., Camerino G., Homfray T., Crosby A.H.,
RA Couper J., David A., Greenfield A., Sinclair A., Ostrer H.;
RT "Mutations in MAP3K1 cause 46,XY disorders of sex development and
RT implicate a common signal transduction pathway in human testis
RT determination.";
RL Am. J. Hum. Genet. 87:898-904(2010).
CC -!- FUNCTION: Component of a protein kinase signal transduction
CC cascade. Activates the ERK and JNK kinase pathways by
CC phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB,
CC the central protein kinases of the NF-kappa-B pathway.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by autophosphorylation on Thr-1400
CC and Thr-1412 following oligomerization.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes through its N-terminus. Oligomerizes
CC after binding MAP4K2 or TRAF2. Interacts with AXIN1. Interacts
CC (via the kinase catalytic domain) with STK38.
CC -!- INTERACTION:
CC P15056:BRAF; NbExp=2; IntAct=EBI-49776, EBI-365980;
CC P61962:DCAF7; NbExp=6; IntAct=EBI-49776, EBI-359808;
CC O75369:FLNB; NbExp=2; IntAct=EBI-49776, EBI-352089;
CC P45985:MAP2K4; NbExp=3; IntAct=EBI-49776, EBI-447868;
CC Q12851:MAP4K2; NbExp=2; IntAct=EBI-49776, EBI-49783;
CC -!- PTM: Autophosphorylated (By similarity).
CC -!- DISEASE: 46,XY sex reversal 6 (SRXY6) [MIM:613762]: A disorder of
CC sex development. Affected individuals have a 46,XY karyotype but
CC present as phenotypically normal females. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SIMILARITY: Contains 1 SWIM-type zinc finger.
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DR EMBL; AC008937; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF042838; AAC97073.1; -; mRNA.
DR EMBL; U29671; AAB05828.1; -; Genomic_DNA.
DR PIR; G01887; G01887.
DR RefSeq; NP_005912.1; NM_005921.1.
DR UniGene; Hs.653654; -.
DR ProteinModelPortal; Q13233; -.
DR SMR; Q13233; 1227-1505.
DR DIP; DIP-27520N; -.
DR IntAct; Q13233; 25.
DR MINT; MINT-143285; -.
DR STRING; 9606.ENSP00000382423; -.
DR BindingDB; Q13233; -.
DR ChEMBL; CHEMBL3956; -.
DR GuidetoPHARMACOLOGY; 2069; -.
DR PhosphoSite; Q13233; -.
DR DMDM; 218512139; -.
DR SWISS-2DPAGE; Q13233; -.
DR PaxDb; Q13233; -.
DR PRIDE; Q13233; -.
DR DNASU; 4214; -.
DR Ensembl; ENST00000399503; ENSP00000382423; ENSG00000095015.
DR GeneID; 4214; -.
DR KEGG; hsa:4214; -.
DR UCSC; uc003jqw.4; human.
DR CTD; 4214; -.
DR GeneCards; GC05P056110; -.
DR H-InvDB; HIX0024789; -.
DR HGNC; HGNC:6848; MAP3K1.
DR HPA; CAB004500; -.
DR MIM; 600982; gene.
DR MIM; 613762; phenotype.
DR neXtProt; NX_Q13233; -.
DR Orphanet; 242; 46,XY complete gonadal dysgenesis.
DR Orphanet; 251510; 46,XY partial gonadal dysgenesis.
DR PharmGKB; PA30592; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000113437; -.
DR HOVERGEN; HBG006302; -.
DR InParanoid; Q13233; -.
DR KO; K04416; -.
DR OMA; STHFTRM; -.
DR OrthoDB; EOG7MSMNV; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13233; -.
DR GeneWiki; MAP3K1; -.
DR GenomeRNAi; 4214; -.
DR NextBio; 16613; -.
DR PRO; PR:Q13233; -.
DR Bgee; Q13233; -.
DR CleanEx; HS_MAP3K1; -.
DR Genevestigator; Q13233; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0008545; F:JUN kinase kinase activity; IEA:Ensembl.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; NAS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl.
DR GO; GO:0043010; P:camera-type eye development; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030838; P:positive regulation of actin filament polymerization; IEA:Ensembl.
DR GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl.
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: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:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
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 InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR007527; Znf_SWIM.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00184; RING; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48371; SSF48371; 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.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS50966; ZF_SWIM; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome; Kinase; Magnesium;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Zinc; Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1512 Mitogen-activated protein kinase kinase
FT kinase 1.
FT /FTId=PRO_0000086240.
FT DOMAIN 1243 1508 Protein kinase.
FT ZN_FING 338 366 SWIM-type.
FT ZN_FING 443 492 RING-type.
FT NP_BIND 1249 1257 ATP (By similarity).
FT COMPBIAS 2 5 Poly-Ala.
FT COMPBIAS 25 29 Poly-Gly.
FT COMPBIAS 36 41 Poly-Ala.
FT COMPBIAS 422 431 Poly-Ser.
FT COMPBIAS 842 847 Poly-Ser.
FT COMPBIAS 942 949 Poly-Thr.
FT COMPBIAS 1182 1187 Poly-Glu.
FT COMPBIAS 1216 1219 Poly-Ile.
FT ACT_SITE 1369 1369 Proton acceptor (By similarity).
FT BINDING 1272 1272 ATP (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 137 137 Phosphoserine (By similarity).
FT MOD_RES 154 154 Phosphoserine.
FT MOD_RES 275 275 Phosphoserine.
FT MOD_RES 292 292 Phosphoserine.
FT MOD_RES 297 297 Phosphoserine.
FT MOD_RES 300 300 Phosphoserine.
FT MOD_RES 507 507 Phosphoserine.
FT MOD_RES 1018 1018 Phosphoserine.
FT MOD_RES 1043 1043 Phosphoserine.
FT MOD_RES 1400 1400 Phosphothreonine; by autocatalysis (By
FT similarity).
FT MOD_RES 1412 1412 Phosphothreonine; by autocatalysis (By
FT similarity).
FT VARIANT 92 92 S -> N.
FT /FTId=VAR_040680.
FT VARIANT 189 189 L -> P (in SRXY6; increases
FT phosphorylation of the downstream target
FT MAPK3/MAPK1 compared to wild-type and
FT enhances binding of RHOA to the mutant
FT MAP3K1 complex).
FT /FTId=VAR_065504.
FT VARIANT 189 189 L -> R (in SRXY6; increases
FT phosphorylation of the downstream targets
FT MAPK14 and MAPK3/MAPK1 compared to wild-
FT type and enhances binding of RHOA to the
FT mutant MAP3K1 complex).
FT /FTId=VAR_065505.
FT VARIANT 211 211 V -> VIQ (in SRXY6).
FT /FTId=VAR_065506.
FT VARIANT 443 443 C -> S.
FT /FTId=VAR_040681.
FT VARIANT 616 616 G -> R (in SRXY6; dbSNP:rs143853590).
FT /FTId=VAR_065507.
FT VARIANT 806 806 D -> N (in dbSNP:rs702689).
FT /FTId=VAR_051636.
FT VARIANT 906 906 V -> I (in dbSNP:rs832582).
FT /FTId=VAR_051637.
FT CONFLICT 20 20 T -> P (in Ref. 2; AAC97073).
FT CONFLICT 37 37 P -> R (in Ref. 2; AAC97073).
FT CONFLICT 120 120 G -> R (in Ref. 2; AAC97073).
FT CONFLICT 351 351 R -> H (in Ref. 2; AAC97073).
FT CONFLICT 845 845 S -> SV (in Ref. 2; AAC97073).
FT CONFLICT 859 859 I -> Y (in Ref. 2; AAC97073).
FT CONFLICT 878 902 DGQQDSFLQASVPNNYLETTENSSP -> QRQQHNSFCRHL
FT FPTTIWKPQRTVPL (in Ref. 2; AAC97073).
FT CONFLICT 933 933 S -> R (in Ref. 2; AAC97073).
FT CONFLICT 1097 1097 C -> L (in Ref. 2; AAC97073).
FT CONFLICT 1104 1107 AVIP -> CCYT (in Ref. 2; AAC97073).
FT CONFLICT 1200 1200 D -> V (in Ref. 2; AAC97073).
SQ SEQUENCE 1512 AA; 164470 MW; 5CB78242295411D9 CRC64;
MAAAAGNRAS SSGFPGARAT SPEAGGGGGA LKASSAPAAA AGLLREAGSG GRERADWRRR
QLRKVRSVEL DQLPEQPLFL AASPPASSTS PSPEPADAAG SGTGFQPVAV PPPHGAASRG
GAHLTESVAA PDSGASSPAA AEPGEKRAPA AEPSPAAAPA GREMENKETL KGLHKMDDRP
EERMIREKLK ATCMPAWKHE WLERRNRRGP VVVKPIPVKG DGSEMNHLAA ESPGEVQASA
ASPASKGRRS PSPGNSPSGR TVKSESPGVR RKRVSPVPFQ SGRITPPRRA PSPDGFSPYS
PEETNRRVNK VMRARLYLLQ QIGPNSFLIG GDSPDNKYRV FIGPQNCSCA RGTFCIHLLF
VMLRVFQLEP SDPMLWRKTL KNFEVESLFQ KYHSRRSSRI KAPSRNTIQK FVSRMSNSHT
LSSSSTSTSS SENSIKDEEE QMCPICLLGM LDEESLTVCE DGCRNKLHHH CMSIWAEECR
RNREPLICPL CRSKWRSHDF YSHELSSPVD SPSSLRAAQQ QTVQQQPLAG SRRNQESNFN
LTHYGTQQIP PAYKDLAEPW IQVFGMELVG CLFSRNWNVR EMALRRLSHD VSGALLLANG
ESTGNSGGSS GSSPSGGATS GSSQTSISGD VVEACCSVLS MVCADPVYKV YVAALKTLRA
MLVYTPCHSL AERIKLQRLL QPVVDTILVK CADANSRTSQ LSISTLLELC KGQAGELAVG
REILKAGSIG IGGVDYVLNC ILGNQTESNN WQELLGRLCL IDRLLLEFPA EFYPHIVSTD
VSQAEPVEIR YKKLLSLLTF ALQSIDNSHS MVGKLSRRIY LSSARMVTTV PHVFSKLLEM
LSVSSSTHFT RMRRRLMAIA DEVEIAEAIQ LGVEDTLDGQ QDSFLQASVP NNYLETTENS
SPECTVHLEK TGKGLCATKL SASSEDISER LASISVGPSS STTTTTTTTE QPKPMVQTKG
RPHSQCLNSS PLSHHSQLMF PALSTPSSST PSVPAGTATD VSKHRLQGFI PCRIPSASPQ
TQRKFSLQFH RNCPENKDSD KLSPVFTQSR PLPSSNIHRP KPSRPTPGNT SKQGDPSKNS
MTLDLNSSSK CDDSFGCSSN SSNAVIPSDE TVFTPVEEKC RLDVNTELNS SIEDLLEASM
PSSDTTVTFK SEVAVLSPEK AENDDTYKDD VNHNQKCKEK MEAEEEEALA IAMAMSASQD
ALPIVPQLQV ENGEDIIIIQ QDTPETLPGH TKAKQPYRED TEWLKGQQIG LGAFSSCYQA
QDVGTGTLMA VKQVTYVRNT SSEQEEVVEA LREEIRMMSH LNHPNIIRML GATCEKSNYN
LFIEWMAGGS VAHLLSKYGA FKESVVINYT EQLLRGLSYL HENQIIHRDV KGANLLIDST
GQRLRIADFG AAARLASKGT GAGEFQGQLL GTIAFMAPEV LRGQQYGRSC DVWSVGCAII
EMACAKPPWN AEKHSNHLAL IFKIASATTA PSIPSHLSPG LRDVALRCLE LQPQDRPPSR
ELLKHPVFRT TW
//
ID M3K1_HUMAN Reviewed; 1512 AA.
AC Q13233;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-DEC-2008, sequence version 4.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 1;
DE EC=2.7.11.25;
DE AltName: Full=MAPK/ERK kinase kinase 1;
DE Short=MEK kinase 1;
DE Short=MEKK 1;
GN Name=MAP3K1; Synonyms=MAPKKK1, MEKK, MEKK1;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 20-1512, FUNCTION, AND INTERACTION WITH
RP MAP2K4.
RX PubMed=9808624;
RA Xia Y., Wu Z., Su B., Murray B., Karin M.;
RT "JNKK1 organizes a MAP kinase module through specific and sequential
RT interactions with upstream and downstream components mediated by its
RT amino-terminal extension.";
RL Genes Dev. 12:3369-3381(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1238-1274.
RC TISSUE=Leukocyte;
RX PubMed=8597633; DOI=10.1007/BF00539003;
RA Vinik B.S., Kay E.S., Fiedorek F.T. Jr.;
RT "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and
RT human chromosome 5.";
RL Mamm. Genome 6:782-783(1995).
RN [4]
RP INTERACTION WITH AXIN1.
RX PubMed=12223491; DOI=10.1074/jbc.M208099200;
RA Rui H.L., Fan E., Zhou H.M., Xu Z., Zhang Y., Lin S.C.;
RT "SUMO-1 modification of the C-terminal KVEKVD of Axin is required for
RT JNK activation but has no effect on Wnt signaling.";
RL J. Biol. Chem. 277:42981-42986(2002).
RN [5]
RP INTERACTION WITH AXIN1.
RX PubMed=15262978; DOI=10.1074/jbc.M404598200;
RA Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C.;
RT "The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal
RT kinase activation by Axin and dishevelled through distinct
RT mechanisms.";
RL J. Biol. Chem. 279:39366-39373(2004).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-154 AND SER-1043, 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 [8]
RP INTERACTION WITH STK38.
RX PubMed=17906693; DOI=10.1038/sj.onc.1210828;
RA Enomoto A., Kido N., Ito M., Morita A., Matsumoto Y., Takamatsu N.,
RA Hosoi Y., Miyagawa K.;
RT "Negative regulation of MEKK1/2 signaling by serine-threonine kinase
RT 38 (STK38).";
RL Oncogene 27:1930-1938(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292; SER-297; SER-300;
RP SER-507 AND SER-1018, AND 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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275 AND SER-292, AND
RP MASS SPECTROMETRY.
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 [12]
RP VARIANTS [LARGE SCALE ANALYSIS] ASN-92 AND SER-443.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [13]
RP VARIANTS SRXY6 PRO-189; ARG-189; ILE-GLN-211 INS AND ARG-616, AND
RP CHARACTERIZATION OF VARIANTS SRXY6 PRO-189 AND ARG-189.
RX PubMed=21129722; DOI=10.1016/j.ajhg.2010.11.003;
RA Pearlman A., Loke J., Le Caignec C., White S., Chin L., Friedman A.,
RA Warr N., Willan J., Brauer D., Farmer C., Brooks E., Oddoux C.,
RA Riley B., Shajahan S., Camerino G., Homfray T., Crosby A.H.,
RA Couper J., David A., Greenfield A., Sinclair A., Ostrer H.;
RT "Mutations in MAP3K1 cause 46,XY disorders of sex development and
RT implicate a common signal transduction pathway in human testis
RT determination.";
RL Am. J. Hum. Genet. 87:898-904(2010).
CC -!- FUNCTION: Component of a protein kinase signal transduction
CC cascade. Activates the ERK and JNK kinase pathways by
CC phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB,
CC the central protein kinases of the NF-kappa-B pathway.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by autophosphorylation on Thr-1400
CC and Thr-1412 following oligomerization.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes through its N-terminus. Oligomerizes
CC after binding MAP4K2 or TRAF2. Interacts with AXIN1. Interacts
CC (via the kinase catalytic domain) with STK38.
CC -!- INTERACTION:
CC P15056:BRAF; NbExp=2; IntAct=EBI-49776, EBI-365980;
CC P61962:DCAF7; NbExp=6; IntAct=EBI-49776, EBI-359808;
CC O75369:FLNB; NbExp=2; IntAct=EBI-49776, EBI-352089;
CC P45985:MAP2K4; NbExp=3; IntAct=EBI-49776, EBI-447868;
CC Q12851:MAP4K2; NbExp=2; IntAct=EBI-49776, EBI-49783;
CC -!- PTM: Autophosphorylated (By similarity).
CC -!- DISEASE: 46,XY sex reversal 6 (SRXY6) [MIM:613762]: A disorder of
CC sex development. Affected individuals have a 46,XY karyotype but
CC present as phenotypically normal females. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SIMILARITY: Contains 1 SWIM-type zinc finger.
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DR EMBL; AC008937; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF042838; AAC97073.1; -; mRNA.
DR EMBL; U29671; AAB05828.1; -; Genomic_DNA.
DR PIR; G01887; G01887.
DR RefSeq; NP_005912.1; NM_005921.1.
DR UniGene; Hs.653654; -.
DR ProteinModelPortal; Q13233; -.
DR SMR; Q13233; 1227-1505.
DR DIP; DIP-27520N; -.
DR IntAct; Q13233; 25.
DR MINT; MINT-143285; -.
DR STRING; 9606.ENSP00000382423; -.
DR BindingDB; Q13233; -.
DR ChEMBL; CHEMBL3956; -.
DR GuidetoPHARMACOLOGY; 2069; -.
DR PhosphoSite; Q13233; -.
DR DMDM; 218512139; -.
DR SWISS-2DPAGE; Q13233; -.
DR PaxDb; Q13233; -.
DR PRIDE; Q13233; -.
DR DNASU; 4214; -.
DR Ensembl; ENST00000399503; ENSP00000382423; ENSG00000095015.
DR GeneID; 4214; -.
DR KEGG; hsa:4214; -.
DR UCSC; uc003jqw.4; human.
DR CTD; 4214; -.
DR GeneCards; GC05P056110; -.
DR H-InvDB; HIX0024789; -.
DR HGNC; HGNC:6848; MAP3K1.
DR HPA; CAB004500; -.
DR MIM; 600982; gene.
DR MIM; 613762; phenotype.
DR neXtProt; NX_Q13233; -.
DR Orphanet; 242; 46,XY complete gonadal dysgenesis.
DR Orphanet; 251510; 46,XY partial gonadal dysgenesis.
DR PharmGKB; PA30592; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000113437; -.
DR HOVERGEN; HBG006302; -.
DR InParanoid; Q13233; -.
DR KO; K04416; -.
DR OMA; STHFTRM; -.
DR OrthoDB; EOG7MSMNV; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q13233; -.
DR GeneWiki; MAP3K1; -.
DR GenomeRNAi; 4214; -.
DR NextBio; 16613; -.
DR PRO; PR:Q13233; -.
DR Bgee; Q13233; -.
DR CleanEx; HS_MAP3K1; -.
DR Genevestigator; Q13233; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0008545; F:JUN kinase kinase activity; IEA:Ensembl.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; NAS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl.
DR GO; GO:0043010; P:camera-type eye development; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030838; P:positive regulation of actin filament polymerization; IEA:Ensembl.
DR GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl.
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: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:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
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 InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR007527; Znf_SWIM.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00184; RING; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48371; SSF48371; 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.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS50966; ZF_SWIM; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome; Kinase; Magnesium;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Zinc; Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1512 Mitogen-activated protein kinase kinase
FT kinase 1.
FT /FTId=PRO_0000086240.
FT DOMAIN 1243 1508 Protein kinase.
FT ZN_FING 338 366 SWIM-type.
FT ZN_FING 443 492 RING-type.
FT NP_BIND 1249 1257 ATP (By similarity).
FT COMPBIAS 2 5 Poly-Ala.
FT COMPBIAS 25 29 Poly-Gly.
FT COMPBIAS 36 41 Poly-Ala.
FT COMPBIAS 422 431 Poly-Ser.
FT COMPBIAS 842 847 Poly-Ser.
FT COMPBIAS 942 949 Poly-Thr.
FT COMPBIAS 1182 1187 Poly-Glu.
FT COMPBIAS 1216 1219 Poly-Ile.
FT ACT_SITE 1369 1369 Proton acceptor (By similarity).
FT BINDING 1272 1272 ATP (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 137 137 Phosphoserine (By similarity).
FT MOD_RES 154 154 Phosphoserine.
FT MOD_RES 275 275 Phosphoserine.
FT MOD_RES 292 292 Phosphoserine.
FT MOD_RES 297 297 Phosphoserine.
FT MOD_RES 300 300 Phosphoserine.
FT MOD_RES 507 507 Phosphoserine.
FT MOD_RES 1018 1018 Phosphoserine.
FT MOD_RES 1043 1043 Phosphoserine.
FT MOD_RES 1400 1400 Phosphothreonine; by autocatalysis (By
FT similarity).
FT MOD_RES 1412 1412 Phosphothreonine; by autocatalysis (By
FT similarity).
FT VARIANT 92 92 S -> N.
FT /FTId=VAR_040680.
FT VARIANT 189 189 L -> P (in SRXY6; increases
FT phosphorylation of the downstream target
FT MAPK3/MAPK1 compared to wild-type and
FT enhances binding of RHOA to the mutant
FT MAP3K1 complex).
FT /FTId=VAR_065504.
FT VARIANT 189 189 L -> R (in SRXY6; increases
FT phosphorylation of the downstream targets
FT MAPK14 and MAPK3/MAPK1 compared to wild-
FT type and enhances binding of RHOA to the
FT mutant MAP3K1 complex).
FT /FTId=VAR_065505.
FT VARIANT 211 211 V -> VIQ (in SRXY6).
FT /FTId=VAR_065506.
FT VARIANT 443 443 C -> S.
FT /FTId=VAR_040681.
FT VARIANT 616 616 G -> R (in SRXY6; dbSNP:rs143853590).
FT /FTId=VAR_065507.
FT VARIANT 806 806 D -> N (in dbSNP:rs702689).
FT /FTId=VAR_051636.
FT VARIANT 906 906 V -> I (in dbSNP:rs832582).
FT /FTId=VAR_051637.
FT CONFLICT 20 20 T -> P (in Ref. 2; AAC97073).
FT CONFLICT 37 37 P -> R (in Ref. 2; AAC97073).
FT CONFLICT 120 120 G -> R (in Ref. 2; AAC97073).
FT CONFLICT 351 351 R -> H (in Ref. 2; AAC97073).
FT CONFLICT 845 845 S -> SV (in Ref. 2; AAC97073).
FT CONFLICT 859 859 I -> Y (in Ref. 2; AAC97073).
FT CONFLICT 878 902 DGQQDSFLQASVPNNYLETTENSSP -> QRQQHNSFCRHL
FT FPTTIWKPQRTVPL (in Ref. 2; AAC97073).
FT CONFLICT 933 933 S -> R (in Ref. 2; AAC97073).
FT CONFLICT 1097 1097 C -> L (in Ref. 2; AAC97073).
FT CONFLICT 1104 1107 AVIP -> CCYT (in Ref. 2; AAC97073).
FT CONFLICT 1200 1200 D -> V (in Ref. 2; AAC97073).
SQ SEQUENCE 1512 AA; 164470 MW; 5CB78242295411D9 CRC64;
MAAAAGNRAS SSGFPGARAT SPEAGGGGGA LKASSAPAAA AGLLREAGSG GRERADWRRR
QLRKVRSVEL DQLPEQPLFL AASPPASSTS PSPEPADAAG SGTGFQPVAV PPPHGAASRG
GAHLTESVAA PDSGASSPAA AEPGEKRAPA AEPSPAAAPA GREMENKETL KGLHKMDDRP
EERMIREKLK ATCMPAWKHE WLERRNRRGP VVVKPIPVKG DGSEMNHLAA ESPGEVQASA
ASPASKGRRS PSPGNSPSGR TVKSESPGVR RKRVSPVPFQ SGRITPPRRA PSPDGFSPYS
PEETNRRVNK VMRARLYLLQ QIGPNSFLIG GDSPDNKYRV FIGPQNCSCA RGTFCIHLLF
VMLRVFQLEP SDPMLWRKTL KNFEVESLFQ KYHSRRSSRI KAPSRNTIQK FVSRMSNSHT
LSSSSTSTSS SENSIKDEEE QMCPICLLGM LDEESLTVCE DGCRNKLHHH CMSIWAEECR
RNREPLICPL CRSKWRSHDF YSHELSSPVD SPSSLRAAQQ QTVQQQPLAG SRRNQESNFN
LTHYGTQQIP PAYKDLAEPW IQVFGMELVG CLFSRNWNVR EMALRRLSHD VSGALLLANG
ESTGNSGGSS GSSPSGGATS GSSQTSISGD VVEACCSVLS MVCADPVYKV YVAALKTLRA
MLVYTPCHSL AERIKLQRLL QPVVDTILVK CADANSRTSQ LSISTLLELC KGQAGELAVG
REILKAGSIG IGGVDYVLNC ILGNQTESNN WQELLGRLCL IDRLLLEFPA EFYPHIVSTD
VSQAEPVEIR YKKLLSLLTF ALQSIDNSHS MVGKLSRRIY LSSARMVTTV PHVFSKLLEM
LSVSSSTHFT RMRRRLMAIA DEVEIAEAIQ LGVEDTLDGQ QDSFLQASVP NNYLETTENS
SPECTVHLEK TGKGLCATKL SASSEDISER LASISVGPSS STTTTTTTTE QPKPMVQTKG
RPHSQCLNSS PLSHHSQLMF PALSTPSSST PSVPAGTATD VSKHRLQGFI PCRIPSASPQ
TQRKFSLQFH RNCPENKDSD KLSPVFTQSR PLPSSNIHRP KPSRPTPGNT SKQGDPSKNS
MTLDLNSSSK CDDSFGCSSN SSNAVIPSDE TVFTPVEEKC RLDVNTELNS SIEDLLEASM
PSSDTTVTFK SEVAVLSPEK AENDDTYKDD VNHNQKCKEK MEAEEEEALA IAMAMSASQD
ALPIVPQLQV ENGEDIIIIQ QDTPETLPGH TKAKQPYRED TEWLKGQQIG LGAFSSCYQA
QDVGTGTLMA VKQVTYVRNT SSEQEEVVEA LREEIRMMSH LNHPNIIRML GATCEKSNYN
LFIEWMAGGS VAHLLSKYGA FKESVVINYT EQLLRGLSYL HENQIIHRDV KGANLLIDST
GQRLRIADFG AAARLASKGT GAGEFQGQLL GTIAFMAPEV LRGQQYGRSC DVWSVGCAII
EMACAKPPWN AEKHSNHLAL IFKIASATTA PSIPSHLSPG LRDVALRCLE LQPQDRPPSR
ELLKHPVFRT TW
//
MIM
600982
*RECORD*
*FIELD* NO
600982
*FIELD* TI
*600982 MITOGEN-ACTIVATED KINASE KINASE KINASE 1; MAP3K1
;;MAP/ERK KINASE KINASE 1; MEKK1;;
read moreMAPKKK1;;
MEK KINASE
*FIELD* TX
DESCRIPTION
MAP3K1, or MEKK1, is a mitogen-activated protein kinase (MAPK) kinase
kinase that regulates the ERK (see 601795) and JNK (see 601158) MAPK
pathways, as well as the transcription factor NF-kappa-B (see 164011)
and the transcriptional coactivator p300 (EP300; 602700). MAP3K1
generates antiapoptotic signaling as a full-length protein, but it
induces apoptosis following cleavage by caspases (see 147678) (summary
by Schlesinger et al., 2002).
CLONING
Xia et al. (1998) cloned human MEKK1 from HeLa, B-cell, and Jurkat cDNA
libraries. The deduced 1,495-amino acid protein has a C-terminal
catalytic domain and shares 83% identity with rat Mekk1. Western blot
analysis detected MEKK1 at an apparent molecular mass of 200 kD in
transfected COS-1 cells.
Xu et al. (1996) cloned rat Mekk1. The deduced 1,493-amino acid rat
Mekk1 protein contains 2 N-terminal proline-rich domains, followed by a
cysteine-rich region, 2 pleckstrin (PLEK; 173570) homology (PH) domains,
and a C-terminal kinase domain. Western blot analysis detected
endogenous MEKK1 at an apparent molecular mass of about 195 kD in human
293 cells. Mekk1 proteins with similar molecular masses were detected in
mouse, rat, and Chinese hamster cell lines. Fractionation of cells
expressing rat Mekk1 revealed that the full-length protein associated
with membranes. A Mekk1 C-terminal catalytic domain fragment associated
with both the soluble fraction and with membranes.
Pearlman et al. (2010) demonstrated high levels of expression of Map3k1
in mouse gonads within 13.5 days postcoitum (dpc), with approximately
equal expression in male and female gonads. Map3k1 expression was also
observed throughout the mouse embryonic gonad at 11.5 dpc, the
sex-determining stage of gonad development. Staining occurred within the
testis cords at 13.5 dpc in a pattern indicative of Sertoli cell
expression.
GENE STRUCTURE
Pearlman et al. (2010) noted that the MAP3K1 gene contains 20 exons.
MAPPING
Vinik et al. (1995) identified DNA sequence and size polymorphisms in
intronic and 3-prime untranslated regions of the mouse Map3k1 gene and
the human MAP3K1 homolog. Using these allele-specific polymorphisms,
they mapped the Map3k1 gene in an intersubspecific backcross to mouse
chromosome 13. They mapped the human MAP3K1 gene to chromosome 5 by
somatic cell hybrid analysis.
GENE FUNCTION
By assaying transfected COS-1 cells, Xia et al. (1998) showed that human
MEKK1 activated JNK1 (MAPK8; 601158) robustly and p38-alpha (MAPK14;
600289) less efficiently, but it had only a marginal effect on ERK2
(MAPK1; 176948). MEKK1 directly and specifically interacted with JNKK1
(MAP2K4; 601335) and activated JNKK1 in cells and in vitro.
Phosphorylation of JNKK1 by MEKK1 disrupted their interaction. MEKK1 and
JNK1 competed for binding to JNKK1. Xia et al. (1998) concluded that
JNKK1 is the preferred MEKK1 substrate.
Gamma-interferon (IFNG; 147570) induces a number of genes, including
MEKK1, to upregulate cellular responses by using specific transcription
factors and the cognate elements (Roy et al., 2002).
Lu et al. (2002) found that the PHD domain of MEKK1, a RING finger-like
structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro
and in vivo. Moreover, both MEKK1 kinase activity and the docking motif
on ERK1 (601795)/ERK2 were involved in ERK1/ERK2 ubiquitination.
Significantly, cells expressing ERK2 with the docking motif mutation
were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions
not only as an upstream activator of ERK and JNK through its kinase
domain, but also as an E3 ligase through its PHD domain, providing a
negative regulatory mechanism for decreasing ERK1/ERK2 activity.
Schlesinger et al. (2002) stated that full-length mouse Mekk1 generates
antiapoptotic signals, while a 91-kD C-terminal Mekk1 fragment induces
apoptosis. They found that caspase-dependent cleavage of Mekk1
relocalized the 91-kD fragment from the particulate fraction to a
soluble cytoplasmic fraction. Schlesinger et al. (2002) concluded that
MEKK1 functions as a molecular switch to regulate apoptosis in a
caspase-dependent manner.
Cytokine signaling is thought to require assembly of multicomponent
signaling complexes at cytoplasmic segments of membrane-embedded
receptors, in which receptor-proximal protein kinases are activated.
Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535)
formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3
(601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular
inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2
(CIAP2, or BIRC3; 601721), IKK-gamma (IKBKG; 300248), and MEKK1. TRAF2,
UBC13, and IKK-gamma were required for complex assembly and activation
of MEKK1 and MAP kinase cascades. However, the kinases were not
activated unless the complex was translocated from the membrane to the
cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al.
(2008) proposed that this 2-stage signaling mechanism may apply to other
innate immune receptors and may account for spatial and temporal
separation of MAPK and IKK signaling.
MOLECULAR GENETICS
- Association with Breast Cancer
Easton et al. (2007) identified an A/C SNP (dbSNP rs889312) in the
MAP3K1 gene that was significantly (p = 7 x 10(-20)) associated with
familial breast cancer (114480) in a 3-stage genomewide association
study of 22,848 cases from 22 studies. Easton et al. (2007) found that
the allele was common in the U.K. population and thus unlikely to confer
increased disease risk individually. However, in combination with other
susceptibility alleles, the SNP may become clinically significant.
In a sample of 10,358 carriers of BRCA1 (113705) or BRCA2 (600185) gene
mutations from 23 studies, Antoniou et al. (2008) did not observe an
overall association between dbSNP rs889312 and increased risk of breast
cancer. However, when the group was stratified, BRCA2 mutation carriers
who also carried the minor allele of the SNP were at slightly increased
risk (hazard ratio of 1.12; p(trend) = 0.02). The authors concluded that
this locus interacts multiplicatively on breast cancer risk in BRCA2
mutation carriers.
- 46,XY Sex Reversal 6
In a French family with 46,XY gonadal dysgenesis mapping to chromosome
5q (SRXY6; 613762), Pearlman et al. (2010) analyzed the MAP3K1 gene and
identified a heterozygous splice site mutation that segregated with
disease in the family (600982.0001). Sequence analysis of MAP3K1 in a
New Zealand family with 46,XY gonadal dysgenesis identified a missense
mutation (600982.0002). Screening of MAP3K1 in 11 sporadic cases
revealed 2 more missense mutations in 2 patients (600982.0003 and
600982.0004, respectively). In cultured primary lymphoblastoid cells
from the French family and 2 sporadic patients, the mutations were found
to alter phosphorylation of the downstream targets p38 (MAPK14; 600289)
and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and to enhance binding of
RHOA (165390) to the MAP3K1 complex.
ANIMAL MODEL
Yujiri et al. (1998) targeted disruption of the gene encoding Mekk1 to
define its function in the regulation of MAP kinase pathways and cell
survival. Mekk1 -/- embryonic stem cells from mice had lost or altered
responses of Jnk to microtubule disruption and cold stress but activated
Jnk normally in response to heat shock, anisomycin, and ultraviolet
irradiation. Activation of Jnk was lost and that of Erk was diminished
in response to hyperosmolarity and serum factors in Mekk1 -/- cells.
Loss of Mekk1 expression resulted in a greater apoptotic response of
cells to hyperosmolarity and microtubule disruption. When activated by
specific stresses that alter cell shape and the cytoskeleton, Mekk1
signals to protect cells from apoptosis.
Minamino et al. (1999) found that Mekk1 -/- mouse embryonic stem
cell-derived cardiac myocytes were extremely sensitive to hydrogen
peroxide-induced apoptosis. Elevated sensitivity was due to enhanced
Tnf-alpha (TNF; 191160) production, which was negatively regulated by
the Mekk1-Jnk pathway in wildtype mice.
The BALB/cGa mouse strain and its descendants produced 2 waves of high
frequency of spontaneous heritable mutations. Juriloff et al. (2005)
determined that one of these mutations, referred to as ophthalmatrophy
(oa) or lidgap-Gates (lg-Ga), is a 27.5-kb deletion of exons 2 to 9 of
the Map3k1 gene. The mutation causes a failure of fetal eyelid
development, resulting in the defect 'open eyelids at birth.' Affected
eyes develop corneal opacity by adulthood.
*FIELD* AV
.0001
46,XY SEX REVERSAL 6
MAP3K1, IVS2AS, T-A, -8
In 5 affected individuals from a large multigenerational French family
with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762),
originally reported by Le Caignec et al. (2003), Pearlman et al. (2010)
identified heterozygosity for a splice acceptor site mutation (634-8T-A)
in intron 2 of MAP3K1, resulting in the insertion of 2 amino acids
in-frame at this site. Two mutation-positive individuals were phenotypic
females who on laparotomy had right-sided streak gonads and left-sided
dysgenetic testes, with a dysgerminoma of the right streak gonad in one
patient and a dysgerminoma and gonadoblastoma of the left dysgenetic
testis in the other patient. The other 3 mutation-positive family
members were phenotypic males, 1 with penile hypospadias and chordee,
and the 2 other with perineal hypospadias, 1 of whom also had chordee.
The ratio of mutant to wildtype transcript was greater than 1 in
lymphoblastoid cells from affected individuals. The mutation was not
found in 100 unrelated French controls of European descent or in the
1000 Genomes Project. In cultured primary lymphoblastoid cells, the
mutation was found to increase phosphorylation of the downstream targets
p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948)
compared to wildtype; coimmunoprecipitation studies demonstrated
enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.
.0002
46,XY SEX REVERSAL 6
MAP3K1, GLY616ARG
In affected individuals from a 3-generation New Zealand family of
European descent with 46,XY gonadal dysgenesis, complete or partial
(SRXY6; 613762), originally reported by Espiner et al. (1970), Pearlman
et al. (2010) identified heterozygosity for a 1846G-A transition in exon
10 of the MAP3K1 gene, resulting in a gly616-to-arg (G616R)
substitution. The mutation was not found in 100 unrelated ethnically
matched controls or in the 1000 Genomes Project. A patient cell line
from this family was not available for analysis.
.0003
46,XY SEX REVERSAL 6
MAP3K1, LEU189PRO
In a sporadic patient with 46,XY complete gonadal dysgenesis (SRXY6;
613762), Pearlman et al. (2010) identified heterozygosity for a 566T-C
transition in exon 2 of the MAP3K1 gene, resulting in a leu189-to-pro
(L189P) substitution within the phylogenetically conserved focal
adhesion kinase (FAK) binding site. The mutation was not found in 100
unrelated ethnically matched controls or in the 1000 Genomes Project. In
cultured primary lymphoblastoid cells, the mutation was found to
increase phosphorylation of the downstream target ERK1 (MAPK3;
601795)/ERK2 (MAPK1; 176948) compared to wildtype, and
coimmunoprecipitation studies demonstrated enhanced binding of RHOA
(165390) to the mutant MAP3K1 complex.
.0004
46,XY SEX REVERSAL 6
MAP3K1, LEU189ARG
In a sporadic patient with 46,XY complete gonadal dysgenesis (613762),
Pearlman et al. (2010) identified heterozygosity for a 566T-G
transversion in exon 2 of the MAP3K1 gene, resulting in a leu189-to-arg
(L189R) substitution within the phylogenetically conserved focal
adhesion kinase (FAK) binding site. The mutation was not found in 100
unrelated ethnically matched controls or in the 1000 Genomes Project. In
cultured primary lymphoblastoid cells, the mutation was found to
increase phosphorylation of the downstream targets p38 (MAPK14; 600289)
and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and
coimmunoprecipitation studies demonstrated enhanced binding of RHOA
(165390) to the mutant MAP3K1 complex.
*FIELD* RF
1. Antoniou, A. C.; Spurdle, A. B.; Sinilnikova, O. M.; Healey, S.;
Pooley, K. A.; Schmutzler, R. K.; Versmold, B.; Engel, C.; Meindl,
A.; Arnold, N.; Hofmann, W.; Sutter, C.; and 80 others: Common
breast cancer-predisposition alleles are associated with breast cancer
risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82:
937-948, 2008.
2. Easton, D. F.; Pooley, K. A.; Dunning, A. M.; Pharoah, P. D. P.;
Thompson, D.; Ballinger, D. G.; Struewing, J. P.; Morrison, J.; Field,
H.; Luben, R.; Wareham, N.; Ahmed, S.; and 93 others: Genome-wide
association study identifies novel breast cancer susceptibility loci. Nature 447:
1087-1093, 2007.
3. Espiner, E. A.; Veale, A. M.; Sands, V. E.; Fitzgerald, P. H.:
Familial syndrome of streak gonads and normal male karyotype in five
phenotypic females. New Eng. J. Med. 283: 6-11, 1970.
4. Juriloff, D. M.; Harris, M. J.; Mah, D. G.: The open-eyelid mutation,
lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene. Genomics 85:
139-142, 2005.
5. Le Caignec, C.; Baron, S.; McElreavey, K.; Joubert, M.; Rival,
J.-M.; Mechinaud, F.; David, A.: 46,XY gonadal dysgenesis: evidence
for autosomal dominant transmission in a large kindred. Am. J. Med.
Genet. 116A: 37-43, 2003.
6. Lu, Z.; Xu, S.; Joazeiro, C.; Cobb, M. H.; Hunter, T.: The PHD
domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination
and degradation of ERK1/2. Molec. Cell 9: 945-956, 2002.
7. Matsuzawa, A.; Tseng, P.-H.; Vallabhapurapu, S.; Luo, J.-L.; Zhang,
W.; Wang, H.; Vignali, D. A. A.; Gallagher, E.; Karin, M.: Essential
cytoplasmic translocation of a cytokine receptor-assembled signaling
complex. Science 321: 663-668, 2008. Note: Erratum: Science 322:
375 only, 2008.
8. Minamino, T.; Yujiri, T.; Papst, P. J.; Chan, E. D.; Johnson, G.
L.; Terada, N.: MEKK1 suppresses oxidative stress-induced apoptosis
of embryonic stem cell-derived cardiac myocytes. Proc. Nat. Acad.
Sci. 96: 15127-15132, 1999.
9. Pearlman, A.; Loke, J.; Le Caignec, C.; White, S.; Chin, L.; Friedman,
A.; Warr, N.; Willan, J.; Brauer, D.; Farmer, C.; Brooks, E.; Oddoux,
C.; and 10 others: Mutations in MAP3K1 cause 46,XY disorders of
sex development and implicate a common signal transduction pathway
in human testis determination. Am. J. Hum. Genet. 87: 898-904, 2010.
10. Roy, S. K.; Hu, J.; Meng, Q.; Xia, Y.; Shapiro, P. S.; Reddy,
S. P. M.; Platanias, L. C.; Lindner, D. J.; Johnson, P. F.; Pritchard,
C.; Pages, G.; Pouyssegur, J.; Kalvakolanu, D. V.: MEKK1 plays a
critical role in activating the transcription factor C/EBP-beta-dependent
gene expression in response to IFN-gamma. Proc. Nat. Acad. Sci. 99:
7945-7950, 2002.
11. Schlesinger, T. K.; Bonvin, C.; Jarpe, M. B.; Fanger, G. R.; Cardinaux,
J.-R.; Johnson, G. L.; Widmann, C.: Apoptosis stimulated by the 91-kDa
caspase cleavage MEKK1 fragment requires translocation to soluble
cellular compartments. J. Biol. Chem. 277: 10283-10291, 2002.
12. Vinik, B. S.; Kay, E. S.; Fiedorek, F. T., Jr.: Mapping of the
MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome
5. Mammalian Genome 6: 782-783, 1995.
13. Xia, Y.; Wu, Z.; Su, B.; Murray, B.; Karin, M.: JNKK1 organizes
a MAP kinase module through specific and sequential interactions with
upstream and downstream components mediated by its amino-terminal
extension. Genes Dev. 12: 3369-3381, 1998.
14. Xu, S.; Robbins, D. J.; Christerson, L. B.; English, J. M.; Vanderbilt,
C. A.; Cobb, M. H.: Cloning of rat MEK kinase 1 cDNA reveals an endogenous
membrane-associated 195-kDa protein with a large regulatory domain. Proc.
Nat. Acad. Sci. 93: 5291-5295, 1996.
15. Yujiri, T.; Sather, S.; Fanger, G. R.; Johnson, G. L.: Role of
MEKK1 in cell survival and activation of JNK and ERK pathways defined
by targeted gene disruption. Science 282: 1911-1914, 1998.
*FIELD* CN
Matthew B. Gross - updated: 4/13/2011
Patricia A. Hartz - updated: 3/30/2011
Marla J. F. O'Neill - updated: 2/16/2011
Paul J. Converse - updated: 8/28/2008
Cassandra L. Kniffin - updated: 4/28/2008
Cassandra L. Kniffin - updated: 7/17/2007
Patricia A. Hartz - updated: 2/2/2005
Stylianos E. Antonarakis - updated: 9/18/2002
Victor A. McKusick - updated: 7/3/2002
Ada Hamosh - updated: 9/20/1999
*FIELD* CD
Victor A. McKusick: 1/15/1996
*FIELD* ED
carol: 08/29/2011
wwang: 4/25/2011
mgross: 4/13/2011
terry: 3/30/2011
terry: 3/18/2011
wwang: 2/23/2011
terry: 2/16/2011
terry: 11/25/2009
alopez: 11/18/2008
mgross: 8/28/2008
wwang: 5/1/2008
ckniffin: 4/28/2008
carol: 8/17/2007
ckniffin: 7/17/2007
mgross: 2/2/2005
mgross: 9/18/2002
cwells: 7/17/2002
terry: 7/3/2002
carol: 9/21/1999
terry: 9/20/1999
mgross: 9/15/1999
dholmes: 3/24/1998
psherman: 3/17/1998
psherman: 3/16/1998
terry: 3/4/1998
terry: 1/17/1997
mark: 5/13/1996
mark: 1/15/1996
*RECORD*
*FIELD* NO
600982
*FIELD* TI
*600982 MITOGEN-ACTIVATED KINASE KINASE KINASE 1; MAP3K1
;;MAP/ERK KINASE KINASE 1; MEKK1;;
read moreMAPKKK1;;
MEK KINASE
*FIELD* TX
DESCRIPTION
MAP3K1, or MEKK1, is a mitogen-activated protein kinase (MAPK) kinase
kinase that regulates the ERK (see 601795) and JNK (see 601158) MAPK
pathways, as well as the transcription factor NF-kappa-B (see 164011)
and the transcriptional coactivator p300 (EP300; 602700). MAP3K1
generates antiapoptotic signaling as a full-length protein, but it
induces apoptosis following cleavage by caspases (see 147678) (summary
by Schlesinger et al., 2002).
CLONING
Xia et al. (1998) cloned human MEKK1 from HeLa, B-cell, and Jurkat cDNA
libraries. The deduced 1,495-amino acid protein has a C-terminal
catalytic domain and shares 83% identity with rat Mekk1. Western blot
analysis detected MEKK1 at an apparent molecular mass of 200 kD in
transfected COS-1 cells.
Xu et al. (1996) cloned rat Mekk1. The deduced 1,493-amino acid rat
Mekk1 protein contains 2 N-terminal proline-rich domains, followed by a
cysteine-rich region, 2 pleckstrin (PLEK; 173570) homology (PH) domains,
and a C-terminal kinase domain. Western blot analysis detected
endogenous MEKK1 at an apparent molecular mass of about 195 kD in human
293 cells. Mekk1 proteins with similar molecular masses were detected in
mouse, rat, and Chinese hamster cell lines. Fractionation of cells
expressing rat Mekk1 revealed that the full-length protein associated
with membranes. A Mekk1 C-terminal catalytic domain fragment associated
with both the soluble fraction and with membranes.
Pearlman et al. (2010) demonstrated high levels of expression of Map3k1
in mouse gonads within 13.5 days postcoitum (dpc), with approximately
equal expression in male and female gonads. Map3k1 expression was also
observed throughout the mouse embryonic gonad at 11.5 dpc, the
sex-determining stage of gonad development. Staining occurred within the
testis cords at 13.5 dpc in a pattern indicative of Sertoli cell
expression.
GENE STRUCTURE
Pearlman et al. (2010) noted that the MAP3K1 gene contains 20 exons.
MAPPING
Vinik et al. (1995) identified DNA sequence and size polymorphisms in
intronic and 3-prime untranslated regions of the mouse Map3k1 gene and
the human MAP3K1 homolog. Using these allele-specific polymorphisms,
they mapped the Map3k1 gene in an intersubspecific backcross to mouse
chromosome 13. They mapped the human MAP3K1 gene to chromosome 5 by
somatic cell hybrid analysis.
GENE FUNCTION
By assaying transfected COS-1 cells, Xia et al. (1998) showed that human
MEKK1 activated JNK1 (MAPK8; 601158) robustly and p38-alpha (MAPK14;
600289) less efficiently, but it had only a marginal effect on ERK2
(MAPK1; 176948). MEKK1 directly and specifically interacted with JNKK1
(MAP2K4; 601335) and activated JNKK1 in cells and in vitro.
Phosphorylation of JNKK1 by MEKK1 disrupted their interaction. MEKK1 and
JNK1 competed for binding to JNKK1. Xia et al. (1998) concluded that
JNKK1 is the preferred MEKK1 substrate.
Gamma-interferon (IFNG; 147570) induces a number of genes, including
MEKK1, to upregulate cellular responses by using specific transcription
factors and the cognate elements (Roy et al., 2002).
Lu et al. (2002) found that the PHD domain of MEKK1, a RING finger-like
structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro
and in vivo. Moreover, both MEKK1 kinase activity and the docking motif
on ERK1 (601795)/ERK2 were involved in ERK1/ERK2 ubiquitination.
Significantly, cells expressing ERK2 with the docking motif mutation
were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions
not only as an upstream activator of ERK and JNK through its kinase
domain, but also as an E3 ligase through its PHD domain, providing a
negative regulatory mechanism for decreasing ERK1/ERK2 activity.
Schlesinger et al. (2002) stated that full-length mouse Mekk1 generates
antiapoptotic signals, while a 91-kD C-terminal Mekk1 fragment induces
apoptosis. They found that caspase-dependent cleavage of Mekk1
relocalized the 91-kD fragment from the particulate fraction to a
soluble cytoplasmic fraction. Schlesinger et al. (2002) concluded that
MEKK1 functions as a molecular switch to regulate apoptosis in a
caspase-dependent manner.
Cytokine signaling is thought to require assembly of multicomponent
signaling complexes at cytoplasmic segments of membrane-embedded
receptors, in which receptor-proximal protein kinases are activated.
Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535)
formed a complex containing adaptor molecules TRAF2 (601895) and TRAF3
(601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), cellular
inhibitor of apoptosis protein-1 (CIAP1, or BIRC2; 601712) and -2
(CIAP2, or BIRC3; 601721), IKK-gamma (IKBKG; 300248), and MEKK1. TRAF2,
UBC13, and IKK-gamma were required for complex assembly and activation
of MEKK1 and MAP kinase cascades. However, the kinases were not
activated unless the complex was translocated from the membrane to the
cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al.
(2008) proposed that this 2-stage signaling mechanism may apply to other
innate immune receptors and may account for spatial and temporal
separation of MAPK and IKK signaling.
MOLECULAR GENETICS
- Association with Breast Cancer
Easton et al. (2007) identified an A/C SNP (dbSNP rs889312) in the
MAP3K1 gene that was significantly (p = 7 x 10(-20)) associated with
familial breast cancer (114480) in a 3-stage genomewide association
study of 22,848 cases from 22 studies. Easton et al. (2007) found that
the allele was common in the U.K. population and thus unlikely to confer
increased disease risk individually. However, in combination with other
susceptibility alleles, the SNP may become clinically significant.
In a sample of 10,358 carriers of BRCA1 (113705) or BRCA2 (600185) gene
mutations from 23 studies, Antoniou et al. (2008) did not observe an
overall association between dbSNP rs889312 and increased risk of breast
cancer. However, when the group was stratified, BRCA2 mutation carriers
who also carried the minor allele of the SNP were at slightly increased
risk (hazard ratio of 1.12; p(trend) = 0.02). The authors concluded that
this locus interacts multiplicatively on breast cancer risk in BRCA2
mutation carriers.
- 46,XY Sex Reversal 6
In a French family with 46,XY gonadal dysgenesis mapping to chromosome
5q (SRXY6; 613762), Pearlman et al. (2010) analyzed the MAP3K1 gene and
identified a heterozygous splice site mutation that segregated with
disease in the family (600982.0001). Sequence analysis of MAP3K1 in a
New Zealand family with 46,XY gonadal dysgenesis identified a missense
mutation (600982.0002). Screening of MAP3K1 in 11 sporadic cases
revealed 2 more missense mutations in 2 patients (600982.0003 and
600982.0004, respectively). In cultured primary lymphoblastoid cells
from the French family and 2 sporadic patients, the mutations were found
to alter phosphorylation of the downstream targets p38 (MAPK14; 600289)
and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and to enhance binding of
RHOA (165390) to the MAP3K1 complex.
ANIMAL MODEL
Yujiri et al. (1998) targeted disruption of the gene encoding Mekk1 to
define its function in the regulation of MAP kinase pathways and cell
survival. Mekk1 -/- embryonic stem cells from mice had lost or altered
responses of Jnk to microtubule disruption and cold stress but activated
Jnk normally in response to heat shock, anisomycin, and ultraviolet
irradiation. Activation of Jnk was lost and that of Erk was diminished
in response to hyperosmolarity and serum factors in Mekk1 -/- cells.
Loss of Mekk1 expression resulted in a greater apoptotic response of
cells to hyperosmolarity and microtubule disruption. When activated by
specific stresses that alter cell shape and the cytoskeleton, Mekk1
signals to protect cells from apoptosis.
Minamino et al. (1999) found that Mekk1 -/- mouse embryonic stem
cell-derived cardiac myocytes were extremely sensitive to hydrogen
peroxide-induced apoptosis. Elevated sensitivity was due to enhanced
Tnf-alpha (TNF; 191160) production, which was negatively regulated by
the Mekk1-Jnk pathway in wildtype mice.
The BALB/cGa mouse strain and its descendants produced 2 waves of high
frequency of spontaneous heritable mutations. Juriloff et al. (2005)
determined that one of these mutations, referred to as ophthalmatrophy
(oa) or lidgap-Gates (lg-Ga), is a 27.5-kb deletion of exons 2 to 9 of
the Map3k1 gene. The mutation causes a failure of fetal eyelid
development, resulting in the defect 'open eyelids at birth.' Affected
eyes develop corneal opacity by adulthood.
*FIELD* AV
.0001
46,XY SEX REVERSAL 6
MAP3K1, IVS2AS, T-A, -8
In 5 affected individuals from a large multigenerational French family
with 46,XY gonadal dysgenesis, complete or partial (SRXY6; 613762),
originally reported by Le Caignec et al. (2003), Pearlman et al. (2010)
identified heterozygosity for a splice acceptor site mutation (634-8T-A)
in intron 2 of MAP3K1, resulting in the insertion of 2 amino acids
in-frame at this site. Two mutation-positive individuals were phenotypic
females who on laparotomy had right-sided streak gonads and left-sided
dysgenetic testes, with a dysgerminoma of the right streak gonad in one
patient and a dysgerminoma and gonadoblastoma of the left dysgenetic
testis in the other patient. The other 3 mutation-positive family
members were phenotypic males, 1 with penile hypospadias and chordee,
and the 2 other with perineal hypospadias, 1 of whom also had chordee.
The ratio of mutant to wildtype transcript was greater than 1 in
lymphoblastoid cells from affected individuals. The mutation was not
found in 100 unrelated French controls of European descent or in the
1000 Genomes Project. In cultured primary lymphoblastoid cells, the
mutation was found to increase phosphorylation of the downstream targets
p38 (MAPK14; 600289) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948)
compared to wildtype; coimmunoprecipitation studies demonstrated
enhanced binding of RHOA (165390) to the mutant MAP3K1 complex.
.0002
46,XY SEX REVERSAL 6
MAP3K1, GLY616ARG
In affected individuals from a 3-generation New Zealand family of
European descent with 46,XY gonadal dysgenesis, complete or partial
(SRXY6; 613762), originally reported by Espiner et al. (1970), Pearlman
et al. (2010) identified heterozygosity for a 1846G-A transition in exon
10 of the MAP3K1 gene, resulting in a gly616-to-arg (G616R)
substitution. The mutation was not found in 100 unrelated ethnically
matched controls or in the 1000 Genomes Project. A patient cell line
from this family was not available for analysis.
.0003
46,XY SEX REVERSAL 6
MAP3K1, LEU189PRO
In a sporadic patient with 46,XY complete gonadal dysgenesis (SRXY6;
613762), Pearlman et al. (2010) identified heterozygosity for a 566T-C
transition in exon 2 of the MAP3K1 gene, resulting in a leu189-to-pro
(L189P) substitution within the phylogenetically conserved focal
adhesion kinase (FAK) binding site. The mutation was not found in 100
unrelated ethnically matched controls or in the 1000 Genomes Project. In
cultured primary lymphoblastoid cells, the mutation was found to
increase phosphorylation of the downstream target ERK1 (MAPK3;
601795)/ERK2 (MAPK1; 176948) compared to wildtype, and
coimmunoprecipitation studies demonstrated enhanced binding of RHOA
(165390) to the mutant MAP3K1 complex.
.0004
46,XY SEX REVERSAL 6
MAP3K1, LEU189ARG
In a sporadic patient with 46,XY complete gonadal dysgenesis (613762),
Pearlman et al. (2010) identified heterozygosity for a 566T-G
transversion in exon 2 of the MAP3K1 gene, resulting in a leu189-to-arg
(L189R) substitution within the phylogenetically conserved focal
adhesion kinase (FAK) binding site. The mutation was not found in 100
unrelated ethnically matched controls or in the 1000 Genomes Project. In
cultured primary lymphoblastoid cells, the mutation was found to
increase phosphorylation of the downstream targets p38 (MAPK14; 600289)
and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) compared to wildtype, and
coimmunoprecipitation studies demonstrated enhanced binding of RHOA
(165390) to the mutant MAP3K1 complex.
*FIELD* RF
1. Antoniou, A. C.; Spurdle, A. B.; Sinilnikova, O. M.; Healey, S.;
Pooley, K. A.; Schmutzler, R. K.; Versmold, B.; Engel, C.; Meindl,
A.; Arnold, N.; Hofmann, W.; Sutter, C.; and 80 others: Common
breast cancer-predisposition alleles are associated with breast cancer
risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82:
937-948, 2008.
2. Easton, D. F.; Pooley, K. A.; Dunning, A. M.; Pharoah, P. D. P.;
Thompson, D.; Ballinger, D. G.; Struewing, J. P.; Morrison, J.; Field,
H.; Luben, R.; Wareham, N.; Ahmed, S.; and 93 others: Genome-wide
association study identifies novel breast cancer susceptibility loci. Nature 447:
1087-1093, 2007.
3. Espiner, E. A.; Veale, A. M.; Sands, V. E.; Fitzgerald, P. H.:
Familial syndrome of streak gonads and normal male karyotype in five
phenotypic females. New Eng. J. Med. 283: 6-11, 1970.
4. Juriloff, D. M.; Harris, M. J.; Mah, D. G.: The open-eyelid mutation,
lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene. Genomics 85:
139-142, 2005.
5. Le Caignec, C.; Baron, S.; McElreavey, K.; Joubert, M.; Rival,
J.-M.; Mechinaud, F.; David, A.: 46,XY gonadal dysgenesis: evidence
for autosomal dominant transmission in a large kindred. Am. J. Med.
Genet. 116A: 37-43, 2003.
6. Lu, Z.; Xu, S.; Joazeiro, C.; Cobb, M. H.; Hunter, T.: The PHD
domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination
and degradation of ERK1/2. Molec. Cell 9: 945-956, 2002.
7. Matsuzawa, A.; Tseng, P.-H.; Vallabhapurapu, S.; Luo, J.-L.; Zhang,
W.; Wang, H.; Vignali, D. A. A.; Gallagher, E.; Karin, M.: Essential
cytoplasmic translocation of a cytokine receptor-assembled signaling
complex. Science 321: 663-668, 2008. Note: Erratum: Science 322:
375 only, 2008.
8. Minamino, T.; Yujiri, T.; Papst, P. J.; Chan, E. D.; Johnson, G.
L.; Terada, N.: MEKK1 suppresses oxidative stress-induced apoptosis
of embryonic stem cell-derived cardiac myocytes. Proc. Nat. Acad.
Sci. 96: 15127-15132, 1999.
9. Pearlman, A.; Loke, J.; Le Caignec, C.; White, S.; Chin, L.; Friedman,
A.; Warr, N.; Willan, J.; Brauer, D.; Farmer, C.; Brooks, E.; Oddoux,
C.; and 10 others: Mutations in MAP3K1 cause 46,XY disorders of
sex development and implicate a common signal transduction pathway
in human testis determination. Am. J. Hum. Genet. 87: 898-904, 2010.
10. Roy, S. K.; Hu, J.; Meng, Q.; Xia, Y.; Shapiro, P. S.; Reddy,
S. P. M.; Platanias, L. C.; Lindner, D. J.; Johnson, P. F.; Pritchard,
C.; Pages, G.; Pouyssegur, J.; Kalvakolanu, D. V.: MEKK1 plays a
critical role in activating the transcription factor C/EBP-beta-dependent
gene expression in response to IFN-gamma. Proc. Nat. Acad. Sci. 99:
7945-7950, 2002.
11. Schlesinger, T. K.; Bonvin, C.; Jarpe, M. B.; Fanger, G. R.; Cardinaux,
J.-R.; Johnson, G. L.; Widmann, C.: Apoptosis stimulated by the 91-kDa
caspase cleavage MEKK1 fragment requires translocation to soluble
cellular compartments. J. Biol. Chem. 277: 10283-10291, 2002.
12. Vinik, B. S.; Kay, E. S.; Fiedorek, F. T., Jr.: Mapping of the
MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome
5. Mammalian Genome 6: 782-783, 1995.
13. Xia, Y.; Wu, Z.; Su, B.; Murray, B.; Karin, M.: JNKK1 organizes
a MAP kinase module through specific and sequential interactions with
upstream and downstream components mediated by its amino-terminal
extension. Genes Dev. 12: 3369-3381, 1998.
14. Xu, S.; Robbins, D. J.; Christerson, L. B.; English, J. M.; Vanderbilt,
C. A.; Cobb, M. H.: Cloning of rat MEK kinase 1 cDNA reveals an endogenous
membrane-associated 195-kDa protein with a large regulatory domain. Proc.
Nat. Acad. Sci. 93: 5291-5295, 1996.
15. Yujiri, T.; Sather, S.; Fanger, G. R.; Johnson, G. L.: Role of
MEKK1 in cell survival and activation of JNK and ERK pathways defined
by targeted gene disruption. Science 282: 1911-1914, 1998.
*FIELD* CN
Matthew B. Gross - updated: 4/13/2011
Patricia A. Hartz - updated: 3/30/2011
Marla J. F. O'Neill - updated: 2/16/2011
Paul J. Converse - updated: 8/28/2008
Cassandra L. Kniffin - updated: 4/28/2008
Cassandra L. Kniffin - updated: 7/17/2007
Patricia A. Hartz - updated: 2/2/2005
Stylianos E. Antonarakis - updated: 9/18/2002
Victor A. McKusick - updated: 7/3/2002
Ada Hamosh - updated: 9/20/1999
*FIELD* CD
Victor A. McKusick: 1/15/1996
*FIELD* ED
carol: 08/29/2011
wwang: 4/25/2011
mgross: 4/13/2011
terry: 3/30/2011
terry: 3/18/2011
wwang: 2/23/2011
terry: 2/16/2011
terry: 11/25/2009
alopez: 11/18/2008
mgross: 8/28/2008
wwang: 5/1/2008
ckniffin: 4/28/2008
carol: 8/17/2007
ckniffin: 7/17/2007
mgross: 2/2/2005
mgross: 9/18/2002
cwells: 7/17/2002
terry: 7/3/2002
carol: 9/21/1999
terry: 9/20/1999
mgross: 9/15/1999
dholmes: 3/24/1998
psherman: 3/17/1998
psherman: 3/16/1998
terry: 3/4/1998
terry: 1/17/1997
mark: 5/13/1996
mark: 1/15/1996
MIM
613762
*RECORD*
*FIELD* NO
613762
*FIELD* TI
#613762 46,XY SEX REVERSAL 6; SRXY6
;;46,XY SEX REVERSAL, PARTIAL OR COMPLETE, MAP3K1-RELATED;;
read more46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, MAP3K1-RELATED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of 46,XY sex reversal is caused by heterozygous mutation in the
MAP3K1 gene (600982) on chromosome 5q11.2.
CLINICAL FEATURES
Sternberg et al. (1968) reported 3 cases of 46,XY females, each in a
different sibship of a family connected through normal females
(proposita, maternal cousin, and maternal aunt).
Espiner et al. (1970) studied a New Zealand kindred of European descent
in which 5 phenotypic females from 3 sibships had a normal XY karyotype
in all stem lines examined and pure gonadal dysgenesis, with bilateral
streak gonads verified at laparotomy. The proband presented at 21 years
of age because she was still growing, and had grown 1.9 cm in height
over the past 6 months. She had undergone pubertal changes, including
some breast development and growth of pubic and axillary hair, between
age 14 and 16 years; menarche occurred at age 15 years, with 4
apparently normal menstrual periods, which then ceased. At age 21 years,
her physical appearance was eunuchoidal, with sparse pubic and axillary
hair; both phenotype and gender role were entirely feminine, and she had
normal female external genitalia and normal uterine cervix by palpation.
The remainder of the examination was normal, with no neck webbing,
cubitus valgus, or other congenital anomaly. Laparotomy revealed a
hypoplastic uterus from which apparently normal fallopian tubes extended
laterally, with gonadal streaks seen on the posterior aspect of the
broad ligaments. Microscopic examination of the fallopian tubes was
normal, but multiple sections of the gonadal streaks showed fibrous
connective tissue arranged in whorls resembling ovarian stroma. Some
vestigial epithelial elements, assumed to be rete tubules, were also
seen, but no germ cells could be identified and Leydig cells were
sparse. The proband had 2 similarly affected older sisters, who were
also evaluated and found to be 46,XY with streak gonads at laparotomy.
In addition, she had 2 apparently unaffected older sisters who had borne
children: buccal smears from a phenotypic daughter of each of them
revealed an XY karyotype, and laparotomy at puberty showed streak gonads
in both cases. Espiner et al. (1970) stated that these familial cases,
with occurrence over 2 generations, could not be due to loss of male
determinants on the Y chromosome (see 400044), but rather, like the
cases reported by Sternberg et al. (1968), were consistent with the
effects of a single gene located on an autosome or on the X chromosome.
Espiner et al. (1970) emphasized that the affected persons were
unusually tall for females. The height of patients with XY gonadal
dysgenesis (unusually great for females) is probably explained by
androgen production in the streak gonad (Rose et al., 1974).
Clitoromegaly is present in some cases.
Le Caignec et al. (2003) described 46,XY gonadal dysgenesis in a large
French kindred with various disorders of sexual development, ranging
from complete female phenotype without ambiguity of the external
genitalia (5 cases) to men with isolated penile or perineal hypospadias
(4 cases), including 2 cases with moderate virilization and 1 case with
ambiguity of the external genitalia. Histologic examination in 7
subjects yielded findings suggestive of complete gonadal dysgenesis in 1
patient, partial gonadal dysgenesis in 3 patients, and mixed gonadal
dysgenesis in 3 patients. Four patients developed gonadal tumors: 2 had
gonadoblastoma, 2 had dysgerminoma, and 1 had an immature teratoma,
i.e., a dysgerminoma with some areas of gonadoblastoma. None of the
affected subjects had other congenital anomalies or dysmorphic features.
Previously reported families had implied an X-linked mode of inheritance
because of the apparent absence of male-to-male transmission; however, a
sex-limited autosomal dominant mode of inheritance affecting only XY
individuals could not be ruled out. Analysis of the pedigree reported by
Le Caignec et al. (2003) indicated an autosomal dominant mode of
inheritance because of male-to-male transmission. Le Caignec et al.
(2003) concluded that this family supports the involvement of at least 1
autosomal gene in nonsyndromic 46,XY gonadal dysgenesis.
MAPPING
Jawaheer et al. (2003) performed a linkage study in the French family
with 46,XY gonadal dysgenesis reported by Le Caignec et al. (2003) and
demonstrated by multipoint parametric analysis a lod score of 4.47,
assuming sex-limited autosomal dominant inheritance with a penetrance of
0.6, for the pericentromeric region of chromosome 5 at approximately 65
cM (57 Mb) from the end of chromosome 5p. The obligatory carrier females
in the kindred showed no abnormality. Jawaheer et al. (2003) concluded
that the pattern of inheritance was probably more complicated than
simple monogenic diseases, because 3 individuals shared the core
haplotype, but did not have obvious clinical abnormalities. They
proposed that in 46,XY carriers the mutant gene is highly penetrant but
can be modified by a second locus. Among unaffected individuals, the
associated phenotypes range from mild hypospadias without impairment of
fertility to partial, or even pure, gonadal dysgenesis. In this family,
a male affected with hypospadias and chordee had 2 offspring: 1 with
perineal hypospadias and chordee and the other with partial gonadal
dysgenesis.
Pearlman et al. (2010) performed linkage analysis in the New Zealand
family with 46,XY gonadal dysgenesis, originally reported by Espiner et
al. (1970), and obtained a maximal lod score of 1.14 at D5S2068. The
combined lod score for this family and the French family with 46,XY
gonadal dysgenesis, originally reported by Le Caignec et al. (2003), was
4.62 at D5S398; the multipoint lod score was 6.21. Recombination
analysis defined a 5-Mb critical interval between D5S1969 and D5S2028.
MOLECULAR GENETICS
In the French family with 46,XY gonadal dysgenesis mapping to chromosome
5q, originally reported by Le Caignec et al. (2003), Pearlman et al.
(2010) analyzed the MAP3K1 gene and identified a heterozygous splice
site mutation that segregated with disease in the family (600982.0001).
Sequence analysis of MAP3K1 in the New Zealand family with 46,XY gonadal
dysgenesis, originally reported by Espiner et al. (1970), identified a
MAP3K1 missense mutation (600982.0002). Screening of the MAP3K1 gene in
11 sporadic cases revealed 2 more missense mutations in 2 patients
(600982.0003 and 600982.0004, respectively).
*FIELD* RF
1. Espiner, E. A.; Veale, A. M.; Sands, V. E.; Fitzgerald, P. H.:
Familial syndrome of streak gonads and normal male karyotype in five
phenotypic females. New Eng. J. Med. 283: 6-11, 1970.
2. Jawaheer, D.; Juo, S.-H. H.; Le Caignec, C.; David, A.; Petit,
C.; Gregersen, P.; Dowbak, S.; Damle, A.; McElreavey, K.; Ostrer,
H.: Mapping a gene for 46,XY gonadal dysgenesis by linkage analysis. Clin.
Genet. 63: 530-535, 2003.
3. Le Caignec, C.; Baron, S.; McElreavey, K.; Joubert, M.; Rival,
J.-M.; Mechinaud, F.; David, A.: 46,XY gonadal dysgenesis: evidence
for autosomal dominant transmission in a large kindred. Am. J. Med.
Genet. 116A: 37-43, 2003.
4. Pearlman, A.; Loke, J.; Le Caignec, C.; White, S.; Chin, L.; Friedman,
A.; Warr, N.; Willan, J.; Brauer, D.; Farmer, C.; Brooks, E.; Oddoux,
C.; and 10 others: Mutations in MAP3K1 cause 46,XY disorders of
sex development and implicate a common signal transduction pathway
in human testis determination. Am. J. Hum. Genet. 87: 898-904, 2010.
5. Rose, L. I.; Underwood, R. H.; Williams, G. H.; Pinkus, G. S.:
Pure gonadal dysgenesis: studies of in vitro androgen metabolism. Am.
J. Med. 57: 957-961, 1974.
6. Sternberg, W. H.; Barclay, D. L.; Kloepfer, H. W.: Familial XY
gonadal dysgenesis. New Eng. J. Med. 278: 695-700, 1968.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Increased height in females
GENITOURINARY:
[External genitalia, male];
Hypospadias, penile;
Hypospadias, perineal;
Chordee;
Ambiguous male external genitalia (rare);
[External genitalia, female];
Normal-appearing female external genitalia;
Clitoromegaly (rare);
[Internal genitalia, male];
Dysgenetic testes;
[Internal genitalia, female];
Streak ovaries;
Uterus hypoplastic to normal;
Fallopian tubes normal
SKIN, NAILS, HAIR:
[Hair];
Sparse axillary and pubic hair;
Hirsutism (rare)
NEOPLASIA:
Gonadoblastoma;
Dysgerminoma
MOLECULAR BASIS:
Caused by mutation in the mitogen-activated kinase kinase kinase
1 gene (MAP3K1, 600982.0001)
*FIELD* CD
Marla J. F. O'Neill: 2/7/2012
*FIELD* ED
joanna: 02/07/2012
*FIELD* CD
Marla J. F. O'Neill: 2/22/2011
*FIELD* ED
alopez: 02/28/2011
alopez: 2/28/2011
wwang: 2/23/2011
*RECORD*
*FIELD* NO
613762
*FIELD* TI
#613762 46,XY SEX REVERSAL 6; SRXY6
;;46,XY SEX REVERSAL, PARTIAL OR COMPLETE, MAP3K1-RELATED;;
read more46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, MAP3K1-RELATED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of 46,XY sex reversal is caused by heterozygous mutation in the
MAP3K1 gene (600982) on chromosome 5q11.2.
CLINICAL FEATURES
Sternberg et al. (1968) reported 3 cases of 46,XY females, each in a
different sibship of a family connected through normal females
(proposita, maternal cousin, and maternal aunt).
Espiner et al. (1970) studied a New Zealand kindred of European descent
in which 5 phenotypic females from 3 sibships had a normal XY karyotype
in all stem lines examined and pure gonadal dysgenesis, with bilateral
streak gonads verified at laparotomy. The proband presented at 21 years
of age because she was still growing, and had grown 1.9 cm in height
over the past 6 months. She had undergone pubertal changes, including
some breast development and growth of pubic and axillary hair, between
age 14 and 16 years; menarche occurred at age 15 years, with 4
apparently normal menstrual periods, which then ceased. At age 21 years,
her physical appearance was eunuchoidal, with sparse pubic and axillary
hair; both phenotype and gender role were entirely feminine, and she had
normal female external genitalia and normal uterine cervix by palpation.
The remainder of the examination was normal, with no neck webbing,
cubitus valgus, or other congenital anomaly. Laparotomy revealed a
hypoplastic uterus from which apparently normal fallopian tubes extended
laterally, with gonadal streaks seen on the posterior aspect of the
broad ligaments. Microscopic examination of the fallopian tubes was
normal, but multiple sections of the gonadal streaks showed fibrous
connective tissue arranged in whorls resembling ovarian stroma. Some
vestigial epithelial elements, assumed to be rete tubules, were also
seen, but no germ cells could be identified and Leydig cells were
sparse. The proband had 2 similarly affected older sisters, who were
also evaluated and found to be 46,XY with streak gonads at laparotomy.
In addition, she had 2 apparently unaffected older sisters who had borne
children: buccal smears from a phenotypic daughter of each of them
revealed an XY karyotype, and laparotomy at puberty showed streak gonads
in both cases. Espiner et al. (1970) stated that these familial cases,
with occurrence over 2 generations, could not be due to loss of male
determinants on the Y chromosome (see 400044), but rather, like the
cases reported by Sternberg et al. (1968), were consistent with the
effects of a single gene located on an autosome or on the X chromosome.
Espiner et al. (1970) emphasized that the affected persons were
unusually tall for females. The height of patients with XY gonadal
dysgenesis (unusually great for females) is probably explained by
androgen production in the streak gonad (Rose et al., 1974).
Clitoromegaly is present in some cases.
Le Caignec et al. (2003) described 46,XY gonadal dysgenesis in a large
French kindred with various disorders of sexual development, ranging
from complete female phenotype without ambiguity of the external
genitalia (5 cases) to men with isolated penile or perineal hypospadias
(4 cases), including 2 cases with moderate virilization and 1 case with
ambiguity of the external genitalia. Histologic examination in 7
subjects yielded findings suggestive of complete gonadal dysgenesis in 1
patient, partial gonadal dysgenesis in 3 patients, and mixed gonadal
dysgenesis in 3 patients. Four patients developed gonadal tumors: 2 had
gonadoblastoma, 2 had dysgerminoma, and 1 had an immature teratoma,
i.e., a dysgerminoma with some areas of gonadoblastoma. None of the
affected subjects had other congenital anomalies or dysmorphic features.
Previously reported families had implied an X-linked mode of inheritance
because of the apparent absence of male-to-male transmission; however, a
sex-limited autosomal dominant mode of inheritance affecting only XY
individuals could not be ruled out. Analysis of the pedigree reported by
Le Caignec et al. (2003) indicated an autosomal dominant mode of
inheritance because of male-to-male transmission. Le Caignec et al.
(2003) concluded that this family supports the involvement of at least 1
autosomal gene in nonsyndromic 46,XY gonadal dysgenesis.
MAPPING
Jawaheer et al. (2003) performed a linkage study in the French family
with 46,XY gonadal dysgenesis reported by Le Caignec et al. (2003) and
demonstrated by multipoint parametric analysis a lod score of 4.47,
assuming sex-limited autosomal dominant inheritance with a penetrance of
0.6, for the pericentromeric region of chromosome 5 at approximately 65
cM (57 Mb) from the end of chromosome 5p. The obligatory carrier females
in the kindred showed no abnormality. Jawaheer et al. (2003) concluded
that the pattern of inheritance was probably more complicated than
simple monogenic diseases, because 3 individuals shared the core
haplotype, but did not have obvious clinical abnormalities. They
proposed that in 46,XY carriers the mutant gene is highly penetrant but
can be modified by a second locus. Among unaffected individuals, the
associated phenotypes range from mild hypospadias without impairment of
fertility to partial, or even pure, gonadal dysgenesis. In this family,
a male affected with hypospadias and chordee had 2 offspring: 1 with
perineal hypospadias and chordee and the other with partial gonadal
dysgenesis.
Pearlman et al. (2010) performed linkage analysis in the New Zealand
family with 46,XY gonadal dysgenesis, originally reported by Espiner et
al. (1970), and obtained a maximal lod score of 1.14 at D5S2068. The
combined lod score for this family and the French family with 46,XY
gonadal dysgenesis, originally reported by Le Caignec et al. (2003), was
4.62 at D5S398; the multipoint lod score was 6.21. Recombination
analysis defined a 5-Mb critical interval between D5S1969 and D5S2028.
MOLECULAR GENETICS
In the French family with 46,XY gonadal dysgenesis mapping to chromosome
5q, originally reported by Le Caignec et al. (2003), Pearlman et al.
(2010) analyzed the MAP3K1 gene and identified a heterozygous splice
site mutation that segregated with disease in the family (600982.0001).
Sequence analysis of MAP3K1 in the New Zealand family with 46,XY gonadal
dysgenesis, originally reported by Espiner et al. (1970), identified a
MAP3K1 missense mutation (600982.0002). Screening of the MAP3K1 gene in
11 sporadic cases revealed 2 more missense mutations in 2 patients
(600982.0003 and 600982.0004, respectively).
*FIELD* RF
1. Espiner, E. A.; Veale, A. M.; Sands, V. E.; Fitzgerald, P. H.:
Familial syndrome of streak gonads and normal male karyotype in five
phenotypic females. New Eng. J. Med. 283: 6-11, 1970.
2. Jawaheer, D.; Juo, S.-H. H.; Le Caignec, C.; David, A.; Petit,
C.; Gregersen, P.; Dowbak, S.; Damle, A.; McElreavey, K.; Ostrer,
H.: Mapping a gene for 46,XY gonadal dysgenesis by linkage analysis. Clin.
Genet. 63: 530-535, 2003.
3. Le Caignec, C.; Baron, S.; McElreavey, K.; Joubert, M.; Rival,
J.-M.; Mechinaud, F.; David, A.: 46,XY gonadal dysgenesis: evidence
for autosomal dominant transmission in a large kindred. Am. J. Med.
Genet. 116A: 37-43, 2003.
4. Pearlman, A.; Loke, J.; Le Caignec, C.; White, S.; Chin, L.; Friedman,
A.; Warr, N.; Willan, J.; Brauer, D.; Farmer, C.; Brooks, E.; Oddoux,
C.; and 10 others: Mutations in MAP3K1 cause 46,XY disorders of
sex development and implicate a common signal transduction pathway
in human testis determination. Am. J. Hum. Genet. 87: 898-904, 2010.
5. Rose, L. I.; Underwood, R. H.; Williams, G. H.; Pinkus, G. S.:
Pure gonadal dysgenesis: studies of in vitro androgen metabolism. Am.
J. Med. 57: 957-961, 1974.
6. Sternberg, W. H.; Barclay, D. L.; Kloepfer, H. W.: Familial XY
gonadal dysgenesis. New Eng. J. Med. 278: 695-700, 1968.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
[Height];
Increased height in females
GENITOURINARY:
[External genitalia, male];
Hypospadias, penile;
Hypospadias, perineal;
Chordee;
Ambiguous male external genitalia (rare);
[External genitalia, female];
Normal-appearing female external genitalia;
Clitoromegaly (rare);
[Internal genitalia, male];
Dysgenetic testes;
[Internal genitalia, female];
Streak ovaries;
Uterus hypoplastic to normal;
Fallopian tubes normal
SKIN, NAILS, HAIR:
[Hair];
Sparse axillary and pubic hair;
Hirsutism (rare)
NEOPLASIA:
Gonadoblastoma;
Dysgerminoma
MOLECULAR BASIS:
Caused by mutation in the mitogen-activated kinase kinase kinase
1 gene (MAP3K1, 600982.0001)
*FIELD* CD
Marla J. F. O'Neill: 2/7/2012
*FIELD* ED
joanna: 02/07/2012
*FIELD* CD
Marla J. F. O'Neill: 2/22/2011
*FIELD* ED
alopez: 02/28/2011
alopez: 2/28/2011
wwang: 2/23/2011