M3K12_MOUSE
ID M3K12_MOUSE Reviewed; 888 AA.
AC Q60700; P70286; Q3TLL7; Q8C4N7; Q8CBX3; Q8CDL6;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 12;
DE EC=2.7.11.25 {ECO:0000269|PubMed:7983011, ECO:0000269|PubMed:8663324};
DE AltName: Full=Dual leucine zipper bearing kinase;
DE Short=DLK;
DE AltName: Full=Leucine-zipper protein kinase;
DE Short=ZPK;
DE AltName: Full=MAPK-upstream kinase;
DE Short=MUK;
DE AltName: Full=Mixed lineage kinase;
GN Name=Map3k12; Synonyms=Zpk;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, FUNCTION, PHOSPHORYLATION,
RP AND TISSUE SPECIFICITY.
RC STRAIN=CD-1; TISSUE=Brain;
RX PubMed=7983011; DOI=10.1016/s0021-9258(18)47353-x;
RA Holzman L.B., Merritt S.E., Fan G.;
RT "Identification, molecular cloning, and characterization of dual leucine
RT zipper bearing kinase. A novel serine/threonine protein kinase that defines
RT a second subfamily of mixed lineage kinases.";
RL J. Biol. Chem. 269:30808-30817(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=ICR X Swiss Webster; TISSUE=Brain;
RX PubMed=8769565; DOI=10.1089/dna.1996.15.631;
RA Blouin R., Beaudoin J., Bergeron P., Nadeau A., Grondin G.;
RT "Cell-specific expression of the ZPK gene in adult mouse tissues.";
RL DNA Cell Biol. 15:631-642(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Diencephalon, Embryonic head, and Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, and Retina;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, SUBCELLULAR LOCATION,
RP PHOSPHORYLATION, MUTAGENESIS OF LYS-185 AND GLU-192, AND TISSUE
RP SPECIFICITY.
RX PubMed=8663324; DOI=10.1074/jbc.271.28.16888;
RA Mata M., Merritt S.E., Fan G., Yu G.G., Holzman L.B.;
RT "Characterization of dual leucine zipper-bearing kinase, a mixed lineage
RT kinase present in synaptic terminals whose phosphorylation state is
RT regulated by membrane depolarization via calcineurin.";
RL J. Biol. Chem. 271:16888-16896(1996).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37; THR-43; SER-640 AND
RP SER-728, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION.
RX PubMed=28111074; DOI=10.1016/j.cell.2016.12.044;
RA Huang Y.A., Zhou B., Wernig M., Suedhof T.C.;
RT "ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and
RT Abeta Secretion.";
RL Cell 168:427-441(2017).
CC -!- FUNCTION: Protein kinase which is part of a non-canonical MAPK
CC signaling pathway (PubMed:7983011, PubMed:8663324, PubMed:28111074).
CC Activated by APOE, enhances the AP-1-mediated transcription of APP, via
CC a MAP kinase signal transduction pathway composed of MAP2K7 and
CC MAPK1/ERK2 and MAPK3/ERK1 (PubMed:28111074). May be an activator of the
CC JNK/SAPK pathway. {ECO:0000269|PubMed:28111074,
CC ECO:0000269|PubMed:7983011, ECO:0000269|PubMed:8663324}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC Evidence={ECO:0000269|PubMed:7983011, ECO:0000269|PubMed:8663324};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25; Evidence={ECO:0000269|PubMed:7983011,
CC ECO:0000269|PubMed:8663324};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- SUBUNIT: Homodimer (PubMed:8663324). Interacts with MBIP (By
CC similarity). {ECO:0000250|UniProtKB:Q12852,
CC ECO:0000269|PubMed:8663324}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane
CC {ECO:0000269|PubMed:8663324}. Note=Behaves essentially as an integral
CC membrane protein. {ECO:0000269|PubMed:8663324}.
CC -!- TISSUE SPECIFICITY: Within the nervous system, predominantly expressed
CC in neurons and enriched in synaptic terminals (PubMed:8663324).
CC Expressed in brain, kidney, lung, heart, testis, gastrointestinal
CC tract, stomach, liver and pancreas (PubMed:8769565, PubMed:7983011).
CC {ECO:0000269|PubMed:7983011, ECO:0000269|PubMed:8663324,
CC ECO:0000269|PubMed:8769565}.
CC -!- DOMAIN: Interacts with MBIP through the leucine-zipper motif.
CC {ECO:0000250|UniProtKB:Q12852}.
CC -!- PTM: Autophosphorylated on Ser/Thr. Phosphorylated in cytosol under
CC basal conditions and dephosphorylated when membrane-associated.
CC {ECO:0000269|PubMed:7983011, ECO:0000269|PubMed:8663324}.
CC -!- PTM: The activity of MAP3K12 can be regulated through its proteasomal
CC degradation. APOE, through a receptor-mediated mechanism, activates
CC MAP3K12 by preventing its proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q12852}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
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DR EMBL; U14636; AAA57280.1; -; mRNA.
DR EMBL; U23789; AAB17123.1; -; mRNA.
DR EMBL; AK029882; BAC26658.1; -; mRNA.
DR EMBL; AK034374; BAC28689.1; -; mRNA.
DR EMBL; AK081623; BAC38274.1; -; mRNA.
DR EMBL; AK166435; BAE38775.1; -; mRNA.
DR EMBL; BC047158; AAH47158.1; -; mRNA.
DR EMBL; BC057572; AAH57572.1; -; mRNA.
DR CCDS; CCDS27885.1; -.
DR PIR; A55318; A55318.
DR RefSeq; NP_001157115.1; NM_001163643.1.
DR RefSeq; NP_033608.3; NM_009582.4.
DR RefSeq; XP_017172113.1; XM_017316624.1.
DR RefSeq; XP_017172114.1; XM_017316625.1.
DR AlphaFoldDB; Q60700; -.
DR SMR; Q60700; -.
DR BioGRID; 204957; 6.
DR IntAct; Q60700; 8.
DR MINT; Q60700; -.
DR STRING; 10090.ENSMUSP00000023812; -.
DR BindingDB; Q60700; -.
DR ChEMBL; CHEMBL4295854; -.
DR iPTMnet; Q60700; -.
DR PhosphoSitePlus; Q60700; -.
DR SwissPalm; Q60700; -.
DR PaxDb; Q60700; -.
DR PRIDE; Q60700; -.
DR ProteomicsDB; 295746; -.
DR ABCD; Q60700; 2 sequenced antibodies.
DR Antibodypedia; 27132; 230 antibodies from 31 providers.
DR DNASU; 26404; -.
DR Ensembl; ENSMUST00000023812; ENSMUSP00000023812; ENSMUSG00000023050.
DR Ensembl; ENSMUST00000169377; ENSMUSP00000133209; ENSMUSG00000023050.
DR Ensembl; ENSMUST00000171565; ENSMUSP00000127629; ENSMUSG00000023050.
DR GeneID; 26404; -.
DR KEGG; mmu:26404; -.
DR UCSC; uc007xwc.2; mouse.
DR CTD; 7786; -.
DR MGI; MGI:1346881; Map3k12.
DR VEuPathDB; HostDB:ENSMUSG00000023050; -.
DR eggNOG; KOG4721; Eukaryota.
DR GeneTree; ENSGT00940000159006; -.
DR HOGENOM; CLU_009311_2_1_1; -.
DR InParanoid; Q60700; -.
DR OMA; PSAWEVC; -.
DR OrthoDB; 938929at2759; -.
DR PhylomeDB; Q60700; -.
DR TreeFam; TF105119; -.
DR BRENDA; 2.7.11.25; 3474.
DR BioGRID-ORCS; 26404; 2 hits in 77 CRISPR screens.
DR ChiTaRS; Map3k12; mouse.
DR PRO; PR:Q60700; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q60700; protein.
DR Bgee; ENSMUSG00000023050; Expressed in ascending aorta and 257 other tissues.
DR ExpressionAtlas; Q60700; baseline and differential.
DR Genevisible; Q60700; MM.
DR GO; GO:0030424; C:axon; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IMP:ARUK-UCL.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; IMP:ARUK-UCL.
DR GO; GO:2000672; P:negative regulation of motor neuron apoptotic process; IMP:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IMP:ARUK-UCL.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; IMP:ARUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0043687; P:post-translational protein modification; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR017419; MAP3K12_MAP3K13.
DR InterPro; IPR027257; MAPKKK12.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF500741; MAPKKK12; 1.
DR PIRSF; PIRSF038165; MAPKKK12_MAPKKK13; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Cytoplasm; Kinase; Magnesium; Membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..888
FT /note="Mitogen-activated protein kinase kinase kinase 12"
FT /id="PRO_0000086262"
FT DOMAIN 158..399
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 26..104
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 423..444
FT /note="Leucine-zipper 1"
FT REGION 476..497
FT /note="Leucine-zipper 2"
FT REGION 557..612
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 654..888
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 772..811
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 850..880
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 269
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 164..172
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 185
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 37
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 43
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 640
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 728
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 185
FT /note="K->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:8663324"
FT MUTAGEN 192
FT /note="E->A: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:8663324"
FT CONFLICT 18
FT /note="V -> A (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
FT CONFLICT 28..29
FT /note="KL -> NV (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
FT CONFLICT 218
FT /note="C -> S (in Ref. 3; BAC26658)"
FT /evidence="ECO:0000305"
FT CONFLICT 382
FT /note="S -> T (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
FT CONFLICT 392
FT /note="Q -> K (in Ref. 3; BAC28689)"
FT /evidence="ECO:0000305"
FT CONFLICT 494..495
FT /note="EQ -> DE (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
FT CONFLICT 517
FT /note="N -> D (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
FT CONFLICT 794
FT /note="E -> G (in Ref. 2; AAB17123)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 888 AA; 96084 MW; CFECF1D34F889ABB CRC64;
MACLHETRTP SPSFGGFVST LSEASMRKLD PDTSDCTPEK DLTPTQCVLR DVVPLGGQGG
GGPSPSPGGE PPPEPFANSV LQLHEQDTGG PGGATGSPES RASRVRADEV RLQCQSGSGF
LEGLFGCLRP VWTMIGKAYS TEHKQQQEDL WEVPFEEILD LQWVGSGAQG AVFLGRFHGE
EVAVKKVRDL KETDIKHLRK LKHPNIITFK GVCTQAPCYC ILMEFCAQGQ LYEVLRAGRP
VTPSLLVDWS MGIAGGMNYL HLHKIIHRDL KSPNMLITYD DVVKISDFGT SKELSDKSTK
MSFAGTVAWM APEVIRNEPV SEKVDIWSFG VVLWELLTGE IPYKDVDSSA IIWGVGSNSL
HLPVPSSCPD GFKILLRQCW NSKPRNRPSF RQILLHLDIA SADVLSTPQE TYFKSQAEWR
EEVKLHFEKI KSEGTCLHRL EEELVMRRRE ELRHALDIRE HYERKLERAN NLYMELNALM
LQLELKEREL LRREQALERR CPGLLKSHPS RGLLHGNTME KLIKKRNVPQ KLSPHSKRPD
ILKTESLLPK LDAALSGVGL PGCPKGPPSP GRSRRGKTRH RKASAKGSCG DLPGLRAALP
PHEPGGLGSP GGLGVGPSAW DACPPALRGL HHDLLLRKMS SSSPDLLSAA LGARGRGATG
GARDPGSPPP PQGDTPPSEG SAPGSTSPDS PGGAKGEPPP PVGPGEGVGL LGTGREGTAG
RGGNRAGSQH LTPAALLYRA AVTRSQKRGI SSEEEEGEVD SEVELPPSQR WPQGPNMRQS
LSTFSSENPS DVEEGTASEP SPSGTPEVGS TNTDERPDER SDDMCSQGSE IPLDLPTSEV
VPEREASSLP MQHQDGQGPN PEDSDCDSTE LDNSNSIDAL RPPASLPP
