LOCUS       NM_032435               5853 bp    mRNA    linear   PRI 07-FEB-2025
DEFINITION  Homo sapiens mitogen-activated protein kinase kinase kinase 21
            (MAP3K21), mRNA.
ACCESSION   NM_032435
VERSION     NM_032435.3
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (bases 1 to 5853)
  AUTHORS   Gong,M., Shen,F., Li,Y., Ming,L. and Hong,L.
  TITLE     MLK4 as an immune marker and its correlation with immune
            infiltration in Cervical squamous cell carcinoma and endocervical
            adenocarcinoma(CESC)
  JOURNAL   PLoS One 18 (8), e0290462 (2023)
   PUBMED   37594950
  REMARK    GeneRIF: MLK4 as an immune marker and its correlation with immune
            infiltration in Cervical squamous cell carcinoma and endocervical
            adenocarcinoma(CESC).
            Publication Status: Online-Only
REFERENCE   2  (bases 1 to 5853)
  AUTHORS   Buljan,M., Ciuffa,R., van Drogen,A., Vichalkovski,A., Mehnert,M.,
            Rosenberger,G., Lee,S., Varjosalo,M., Pernas,L.E., Spegg,V.,
            Snijder,B., Aebersold,R. and Gstaiger,M.
  TITLE     Kinase Interaction Network Expands Functional and Disease Roles of
            Human Kinases
  JOURNAL   Mol Cell 79 (3), 504-520 (2020)
   PUBMED   32707033
REFERENCE   3  (bases 1 to 5853)
  AUTHORS   Li,Y., Zuo,H., Wang,H. and Hu,A.
  TITLE     Decrease of MLK4 prevents hepatocellular carcinoma (HCC) through
            reducing metastasis and inducing apoptosis regulated by ROS/MAPKs
            signaling
  JOURNAL   Biomed Pharmacother 116, 108749 (2019)
   PUBMED   31071576
  REMARK    GeneRIF: MLK4 was over-expressed in tumor samples of Hepatocellular
            carcinoma patients.
            Erratum:[Biomed Pharmacother. 2020 Mar;123:109815. doi:
            10.1016/j.biopha.2020.109815.. PMID: 31932124]
REFERENCE   4  (bases 1 to 5853)
  AUTHORS   Marusiak,A.A., Prelowska,M.K., Mehlich,D., Lazniewski,M.,
            Kaminska,K., Gorczynski,A., Korwat,A., Sokolowska,O.,
            Kedzierska,H., Golab,J., Biernat,W., Plewczynski,D., Brognard,J.
            and Nowis,D.
  TITLE     Upregulation of MLK4 promotes migratory and invasive potential of
            breast cancer cells
  JOURNAL   Oncogene 38 (15), 2860-2875 (2019)
   PUBMED   30552384
  REMARK    GeneRIF: High expression of MLK4 promotes migratory and invasive
            phenotype.
REFERENCE   5  (bases 1 to 5853)
  AUTHORS   Blessing,N.A., Kasturirangan,S., Zink,E.M., Schroyer,A.L. and
            Chadee,D.N.
  TITLE     Osmotic and heat stress-dependent regulation of MLK4beta and MLK3
            by the CHIP E3 ligase in ovarian cancer cells
  JOURNAL   Cell Signal 39, 66-73 (2017)
   PUBMED   28757353
  REMARK    GeneRIF: These results suggest that in the early response to
            stressful stimuli, MLK4beta-MLK3 binding is important for
            regulating MLK3 activity and MAPK signalling, and after prolonged
            periods of stress exposure, MLK4beta and MLK3 proteins decline via
            CHIP-dependent degradation.
REFERENCE   6  (bases 1 to 5853)
  AUTHORS   Martini,M., Russo,M., Lamba,S., Vitiello,E., Crowley,E.H.,
            Sassi,F., Romanelli,D., Frattini,M., Marchetti,A. and Bardelli,A.
  TITLE     Mixed lineage kinase MLK4 is activated in colorectal cancers where
            it synergistically cooperates with activated RAS signaling in
            driving tumorigenesis
  JOURNAL   Cancer Res 73 (6), 1912-1921 (2013)
   PUBMED   23319808
  REMARK    GeneRIF: In establishing the role of MLK4 in intracellular
            signaling, we show it directly phosphorylates MEK1 (MAP2K1) and
            that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells
REFERENCE   7  (bases 1 to 5853)
  AUTHORS   Divaris,K., Monda,K.L., North,K.E., Olshan,A.F., Lange,E.M.,
            Moss,K., Barros,S.P., Beck,J.D. and Offenbacher,S.
  TITLE     Genome-wide association study of periodontal pathogen colonization
  JOURNAL   J Dent Res 91 (7 Suppl), 21S-28S (2012)
   PUBMED   22699663
REFERENCE   8  (bases 1 to 5853)
  AUTHORS   Seit-Nebi,A., Cheng,W., Xu,H. and Han,J.
  TITLE     MLK4 has negative effect on TLR4 signaling
  JOURNAL   Cell Mol Immunol 9 (1), 27-33 (2012)
   PUBMED   21602844
  REMARK    GeneRIF: MLK4 is a negative regulator of TLR4 signaling.
REFERENCE   9  (bases 1 to 5853)
  AUTHORS   Grassi,M.A., Tikhomirov,A., Ramalingam,S., Below,J.E., Cox,N.J. and
            Nicolae,D.L.
  TITLE     Genome-wide meta-analysis for severe diabetic retinopathy
  JOURNAL   Hum Mol Genet 20 (12), 2472-2481 (2011)
   PUBMED   21441570
REFERENCE   10 (bases 1 to 5853)
  AUTHORS   Bandyopadhyay,S., Chiang,C.Y., Srivastava,J., Gersten,M., White,S.,
            Bell,R., Kurschner,C., Martin,C., Smoot,M., Sahasrabudhe,S.,
            Barber,D.L., Chanda,S.K. and Ideker,T.
  TITLE     A human MAP kinase interactome
  JOURNAL   Nat Methods 7 (10), 801-805 (2010)
   PUBMED   20936779
COMMENT     VALIDATED REFSEQ: This record has undergone validation or
            preliminary review. The reference sequence was derived from
            AL133380.5 and AJ311798.1.
            
            On Nov 22, 2018 this sequence version replaced NM_032435.2.
            
            Sequence Note: This RefSeq transcript and protein were derived from
            genomic sequence to make the sequence consistent with the reference
            genome assembly. The genomic coordinates used for the transcript
            record were based on transcript alignments.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: AJ311798.1, BC136648.1 [ECO:0000332]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match     :: ENST00000366624.8/ ENSP00000355583.3
            RefSeq Select criteria :: based on single protein-coding transcript
            ##RefSeq-Attributes-END##
            COMPLETENESS: full length.
PRIMARY     REFSEQ_SPAN         PRIMARY_IDENTIFIER PRIMARY_SPAN        COMP
            1-44                AL133380.5         40710-40753
            45-1110             AL133380.5         40754-41819
            1111-1291           AL133380.5         59428-59608
            1292-1440           AL133380.5         66793-66941
            1441-1616           AL133380.5         67822-67997
            1617-2364           AJ311798.1         1573-2320
            2365-3009           AL133380.5         92052-92696
            3010-5853           AL133380.5         95291-98134
FEATURES             Location/Qualifiers
     source          1..5853
                     /organism="Homo sapiens"
                     /mol_type="mRNA"
                     /db_xref="taxon:9606"
                     /chromosome="1"
                     /map="1q42.2"
     gene            1..5853
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /note="mitogen-activated protein kinase kinase kinase 21"
                     /db_xref="GeneID:84451"
                     /db_xref="HGNC:HGNC:29798"
                     /db_xref="MIM:614793"
     exon            1..1110
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     CDS             306..3416
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /EC_number="2.7.11.25"
                     /note="mitogen-activated protein kinase kinase kinase
                     MLK4; mixed lineage kinase 4"
                     /codon_start=1
                     /product="mitogen-activated protein kinase kinase kinase
                     21"
                     /protein_id="NP_115811.2"
                     /db_xref="CCDS:CCDS1598.1"
                     /db_xref="GeneID:84451"
                     /db_xref="HGNC:HGNC:29798"
                     /db_xref="MIM:614793"
                     /translation="MALRGAAGATDTPVSSAGGAPGGSASSSSTSSGGSASAGAGLWA
                     ALYDYEARGEDELSLRRGQLVEVLSQDAAVSGDEGWWAGQVQRRLGIFPANYVAPCRP
                     AASPAPPPSRPSSPVHVAFERLELKELIGAGGFGQVYRATWQGQEVAVKAARQDPEQD
                     AAAAAESVRREARLFAMLRHPNIIELRGVCLQQPHLCLVLEFARGGALNRALAAANAA
                     PDPRAPGPRRARRIPPHVLVNWAVQIARGMLYLHEEAFVPILHRDLKSSNILLLEKIE
                     HDDICNKTLKITDFGLAREWHRTTKMSTAGTYAWMAPEVIKSSLFSKGSDIWSYGVLL
                     WELLTGEVPYRGIDGLAVAYGVAVNKLTLPIPSTCPEPFAKLMKECWQQDPHIRPSFA
                     LILEQLTAIEGAVMTEMPQESFHSMQDDWKLEIQQMFDELRTKEKELRSREEELTRAA
                     LQQKSQEELLKRREQQLAEREIDVLERELNILIFQLNQEKPKVKKRKGKFKRSRLKLK
                     DGHRISLPSDFQHKITVQASPNLDKRRSLNSSSSSPPSSPTMMPRLRAIQLTSDESNK
                     TWGRNTVFRQEEFEDVKRNFKKKGCTWGPNSIQMKDRTDCKERIRPLSDGNSPWSTIL
                     IKNQKTMPLASLFVDQPGSCEEPKLSPDGLEHRKPKQIKLPSQAYIDLPLGKDAQREN
                     PAEAESWEEAASANAATVSIEMTPTNSLSRSPQRKKTESALYGCTVLLASVALGLDLR
                     ELHKAQAAEEPLPKEEKKKREGIFQRASKSRRSASPPTSLPSTCGEASSPPSLPLSSA
                     LGILSTPSFSTKCLLQMDSEDPLVDSAPVTCDSEMLTPDFCPTAPGSGREPALMPRLD
                     TDCSVSRNLPSSFLQQTCGNVPYCASSKHRPSHHRRTMSDGNPTPTGATIISATGASA
                     LPLCPSPAPHSHLPREVSPKKHSTVHIVPQRRPASLRSRSDLPQAYPQTAVSQLAQTA
                     CVVGRPGPHPTQFLAAKERTKSHVPSLLDADVEGQSRDYTVPLCRMRSKTSRPSIYEL
                     EKEFLS"
     exon            1111..1291
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            1292..1440
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            1441..1616
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            1617..1857
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            1858..1980
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            1981..2131
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            2132..2229
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            2230..3009
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     exon            3010..5853
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /inference="alignment:Splign:2.1.0"
     regulatory      4611..4616
                     /regulatory_class="polyA_signal_sequence"
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /note="hexamer: AATAAA"
     polyA_site      4631
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
     regulatory      5820..5825
                     /regulatory_class="polyA_signal_sequence"
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /note="hexamer: AATAAA"
     polyA_site      5853
                     /gene="MAP3K21"
                     /gene_synonym="dJ862P8.3; MLK4"
                     /note="major polyA site"
ORIGIN      
        1 gtcccaggct ctggctaagg agcgcgcggc gggcgggccg gccgcagggc ctgggcacga
       61 ccatggtggg acgtcgcccg cggcttcggg gaccgctgcg gcagcagagg cggctggcca
      121 ggaacgcggg ccgaggctgg accctttggg cagctagccc gtgatctctg ccgtcaccga
      181 tcgcgattcc taccccctcg ccttcccccg gcgccgacgg ccacaccgcc ggacgatgcg
      241 cgcccgcggc cgcccgggag gctgagccca gcttcccgct ccgccttccc cgcgcagctg
      301 cccccatggc tttgcggggc gccgcgggag cgaccgacac cccggtgtcc tcggccgggg
      361 gagcccccgg cggctcagcg tcctcgtcgt ccacctcctc gggcggctcg gcctcggcgg
      421 gcgcggggct gtgggccgcg ctctatgact acgaggctcg cggcgaggac gagctgagcc
      481 tgcggcgcgg ccagctggtg gaggtgctgt cgcaggacgc cgccgtgtcg ggcgacgagg
      541 gctggtgggc aggccaggtg cagcggcgcc tcggcatctt ccccgccaac tacgtggctc
      601 cctgccgccc ggccgccagc cccgcgccgc cgccctcgcg gcccagctcc ccggtacacg
      661 tcgccttcga gcggctggag ctgaaggagc tcatcggcgc tgggggcttc gggcaggtgt
      721 accgcgccac ctggcagggc caggaggtgg ccgtgaaggc ggcgcgccag gacccggagc
      781 aggacgcggc ggcggctgcc gagagcgtgc ggcgcgaggc tcggctcttc gccatgctgc
      841 ggcaccccaa catcatcgag ctgcgcggcg tgtgcctgca gcagccgcac ctctgcctgg
      901 tgctggagtt cgcccgcggc ggagcgctca accgagcgct ggccgctgcc aacgccgccc
      961 cggacccgcg cgcgcccggc ccccgccgcg cgcgccgcat ccctccgcac gtgctggtca
     1021 actgggccgt gcagatagcg cggggcatgc tctacctgca tgaggaggcc ttcgtgccca
     1081 tcctgcaccg ggacctcaag tccagcaaca ttttgctact tgagaagata gaacatgatg
     1141 acatctgcaa taaaactttg aagattacag attttgggtt ggcgagggaa tggcacagga
     1201 ccaccaaaat gagcacagca ggcacctatg cctggatggc ccccgaagtg atcaagtctt
     1261 ccttgttttc taagggaagc gacatctgga gctatggagt gctgctgtgg gaactgctca
     1321 ccggagaagt cccctatcgg ggcattgatg gcctcgccgt ggcttatggg gtagcagtca
     1381 ataaactcac tttgcccatt ccatccacct gccctgagcc gtttgccaag ctcatgaaag
     1441 aatgctggca acaagaccct catattcgtc catcgtttgc cttaattctc gaacagttga
     1501 ctgctattga aggggcagtg atgactgaga tgcctcaaga atcttttcat tccatgcaag
     1561 atgactggaa actagaaatt caacaaatgt ttgatgagtt gagaacaaag gaaaaggagc
     1621 tgcgatcccg ggaagaggag ctgactcggg cggctctgca gcagaagtct caggaggagc
     1681 tgctaaagcg gcgtgagcag cagctggcag agcgcgagat cgacgtgctg gagcgggaac
     1741 ttaacattct gatattccag ctaaaccagg agaagcccaa ggtaaagaag aggaagggca
     1801 agtttaagag aagtcgttta aagctcaaag atggacatcg aatcagttta ccttcagatt
     1861 tccagcacaa gataaccgtg caggcctctc ccaacttgga caaacggcgg agcctgaaca
     1921 gcagcagttc cagtcccccg agcagcccca caatgatgcc ccgactccga gccatacagt
     1981 tgacttcaga tgaaagcaat aaaacttggg gaaggaacac agtctttcga caagaagaat
     2041 ttgaggatgt aaaaaggaat tttaagaaaa aaggttgtac ctggggacca aattccattc
     2101 aaatgaaaga tagaacagat tgcaaagaaa ggataagacc tctctccgat ggcaacagtc
     2161 cttggtcaac tatcttaata aaaaatcaga aaaccatgcc cttggcttca ttgtttgtgg
     2221 accagccagg gtcctgtgaa gagccaaaac tttcccctga tggattagaa cacagaaaac
     2281 caaaacaaat aaaattgcct agtcaggcct acattgatct acctcttggg aaagatgctc
     2341 agagagagaa tcctgcagaa gctgaaagct gggaggaggc agcctctgcg aatgctgcca
     2401 cagtctccat tgagatgact cctacgaata gtctgagtag atccccccag agaaagaaaa
     2461 cggagtcagc tctgtatggg tgcaccgtcc ttctggcatc ggtggctctg ggactggacc
     2521 tcagagagct tcataaagca caggctgctg aagaaccgtt gcccaaggaa gagaagaaga
     2581 aacgagaggg aatcttccag cgggcttcca agtcccgcag aagcgccagt cctcccacaa
     2641 gcctgccatc cacctgtggg gaggccagca gcccaccctc cctgccactg tcaagtgccc
     2701 tgggcatcct ctccacacct tctttctcca caaagtgcct gctgcagatg gacagtgaag
     2761 atccactggt ggacagtgca cctgtcactt gtgactctga gatgctcact ccggattttt
     2821 gtcccactgc cccaggaagt ggtcgtgagc cagccctcat gccaagactt gacactgatt
     2881 gtagtgtatc aagaaacttg ccgtcttcct tcctacagca gacatgtggg aatgtacctt
     2941 actgtgcttc ttcaaaacat agaccgtcac atcacagacg gaccatgtct gatggaaatc
     3001 cgaccccaac tggtgcaact attatctcag ccactggagc ctctgcactg ccactctgcc
     3061 cctcacctgc tcctcacagt catctgccaa gggaggtctc acccaagaag cacagcactg
     3121 tccacatcgt gcctcagcgt cgccctgcct ccctgagaag ccgctcagat ctgcctcagg
     3181 cttacccaca gacagcagtg tctcagctgg cacagactgc ctgtgtagtg ggtcgcccag
     3241 gaccacatcc cacccaattc ctcgctgcca aggagagaac taaatcccat gtgccttcat
     3301 tactggatgc tgacgtggaa ggtcagagca gggactacac tgtgccactg tgcagaatga
     3361 ggagcaaaac cagccggcca tctatatatg aactggagaa agaattcctg tcttaaacta
     3421 agtgccttac tgttgtttaa gcattttttt aaggtgaaca aatgaacaca atgtatctac
     3481 ctttgaactg tttcatgctg ctgtgttttc aaaagctgtg gccatgttcc taaattagta
     3541 agatatatcc agcttctcaa aaaatgtata tgattgctgt tagccatgtc tattgttttt
     3601 cctctggatt cttttcttat aacttggaat acacaaaagt gtaaaacaag agatgtgcac
     3661 caatgaaaac tatgctgggt cgaattacct tcagcacaat gttaatgttt ttgttctcat
     3721 ttatgccttt gtccatttgc acacaacaga aattgtaatg agcttcacta tttttgtttc
     3781 tttccttcct tttttttctt ttttcctttc tttccttttt cttgtcttgt ttcttgtttt
     3841 tttttcttgt agtttctttt cttaattgtc atttttgcaa caaaaagcca agaaagagct
     3901 ttagtttctt ggcaagaata atgtgatatt agtaagtaaa ggtcttaaaa gtctgacgac
     3961 tggaatagat ataaagtcct gtttaaacta cctaaccttg gctgtgggcc gataatgcat
     4021 atgtccagtt ctcacttaaa ttatgcaatg atatttctct ctgaggaaat tatacggaat
     4081 gtaacttata aaagctttac tgaatataag ttataagcat tttattcatt agaactccaa
     4141 aatagatgtt caaagttcag tccttgccat ttgactgaga ccacatggtg tgccccttga
     4201 gtgaggctaa tctttaggtt tttcctatag aaaacattct tcctccatca gtagcccttt
     4261 atttgatatt cagaagtgga aagctttttc attctccagt agaactttta aaaattgtta
     4321 cagataccta gctcttcaca gatatcatgt actgtaaaca gtcatgtgtc ttaattttat
     4381 tttctctatt tgagtgcata attatcctaa taatcccaaa gacactgaca actcaaggaa
     4441 cagcagtaca gtactattag aagttaagta tgttgttgtt atttcacatt tcatttaatt
     4501 gtggataaat gttagacatc tgttgaaata agctcatatg gtggaaacga caactatatt
     4561 atgaattatt ttcagaaatg gatctttgaa tagcagatca ggatttaaat aataaaatta
     4621 tctatgaatc acttttatgg tcatacatat atgatacaaa tccagagtta ttggtgcaga
     4681 aatggctacc cgagagcttg gtaaatttgc cttggtttct tatgttaaat gtattgtgct
     4741 tcccttctgt ctctagaatg tggctcttca gaagacagac aatcgacatt taaatttttc
     4801 caaacaatga aaaactaaat taaaaacatt gcttgatatt tcatttaaaa ttgcaccttg
     4861 cttaaggttt actgaataac tgaaatgtca gcaatttaaa ataaattcaa ttgtgtgata
     4921 aaatatctca cctataatag aagaaaagga aaatcatatt atttggcaat tttgcagcat
     4981 tgtggttgcc taacaggtat atccagcaga tgagaaacag tatgaaagga ttgtattaac
     5041 atggtaagtt ttgccctaag gaaaacgatc ttgcattctg gattcttgca gcaaagtctc
     5101 agatacttaa tacgttttct tgttttatca tctgttctat gattcggctt cactttgtgt
     5161 ggttattgaa ttatgtaaca gagatttggt tttcccaaaa tgttatcaca tttgaaacta
     5221 tgattgcttt gtgttcagtc cttttggaac acgtagcttc cagcttaagg gtagagaaat
     5281 atatacctaa aatcatcaat acatgaaaga aaaaggatgg aaactatgtc ctcagtttta
     5341 cttctaccaa aacatccctg tatgtgtgtg catgtatgtt ggcgtgtgtg tgtgtgcatg
     5401 catattagta aatgtgtgtt tgcatgtgtg tgttggggag tgtatgtgat ctgggtgttt
     5461 gtttatctct gttattattc ccctttagct ttattttagt caactctaca ttatgatgaa
     5521 tttcaaaatg aagctgtatt aaaataattg taatataaca attcaatctc acatgttact
     5581 gcagatagtt aacttttgct gcaatctatt gtacatttgc aattttctgt gttagtaaac
     5641 ttagcagaat ctggttattt atttttgtgt aggcttaatg ttcactgaaa gataagtcaa
     5701 ttactgttag taaaaaatta aggtactctc actgcagaga tttaaggcct gggcctaatg
     5761 tgctgtatta tgaagccttg tgactgaaaa atatgtttac atatgttgtc tattttttta
     5821 ataaactttt atagctggtc tatttgctca gta
//
