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    MAP3K12 mitogen-activated protein kinase kinase kinase 12 [ Homo sapiens (human) ]

    Gene ID: 7786, updated on 6-Jun-2024

    Summary

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    Official Symbol
    MAP3K12provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 12provided by HGNC
    Primary source
    HGNC:HGNC:6851
    See related
    Ensembl:ENSG00000139625 MIM:600447; AllianceGenome:HGNC:6851
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    DLK; MUK; ZPK; ZPKP1; MEKK12; HP09298
    Summary
    This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.[provided by RefSeq, Jul 2010]
    Expression
    Ubiquitous expression in urinary bladder (RPKM 14.0), brain (RPKM 12.1) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP3K12 in Genome Data Viewer
    Location:
    12q13.13
    Exon count:
    19
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 12 NC_000012.12 (53479669..53501539, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 12 NC_060936.1 (53445716..53466177, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 12 NC_000012.11 (53873453..53893242, complement)

    Chromosome 12 - NC_000012.12Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid active region 6422 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4511 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4512 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4513 Neighboring gene proline rich 13 Neighboring gene poly(rC) binding protein 2 Neighboring gene PCBP2 overlapping transcript 1 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:53876139-53876652 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4514 Neighboring gene Sharpr-MPRA regulatory region 1043 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4515 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 6423 Neighboring gene Sharpr-MPRA regulatory region 3466 Neighboring gene ReSE screen-validated silencer GRCh37_chr12:53902821-53903053 Neighboring gene uncharacterized LOC100652999 Neighboring gene ATF7-NPFF readthrough Neighboring gene ReSE screen-validated silencer GRCh37_chr12:53909665-53909906 Neighboring gene TARBP2 subunit of RISC loading complex Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:53910873-53911372 Neighboring gene neuropeptide FF-amide peptide precursor Neighboring gene activating transcription factor 7

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase. Oetjen E. Arch Pharm (Weinheim), 2016 Jun. PMID 27100796
    2. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. Patel S, et al. J Med Chem, 2015 Jan 8. PMID 25341110
    3. Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrest. Daviau A, et al. Biochem Biophys Res Commun, 2011 Sep 23. PMID 21893036
    4. The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation. Robitaille H, et al. J Biol Chem, 2005 Apr 1. PMID 15695824
    5. Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation. Graves PR, et al. J Biol Chem, 2005 Mar 11. PMID 15611134

    See all (45) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress cell proliferation and invasion in prostate cancer by regulating MAP3K12
      Title: Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress in prostate cancer progression by regulating MAP3K12.
    2. LZK cooperates with DLK to promote retinal ganglion cell death in response to axon injury.
      Title: Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons.
    3. REVIEW: Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase
      Title: Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase.
    4. miR-130a inhibited the JNK pathway by targeting MAP3K12, contributing to its anti-apoptotic effect and the maintenance of diabetic endothelial progenitor cell function.
      Title: MicroRNA-130a Targets MAP3K12 to Modulate Diabetic Endothelial Progenitor Cell Function.
    5. Data suggest that specific pharmacological inhibition of dual leucine zipper kinase (DLK, MAP3K12) may have therapeutic potential in multiple indications of neuronal degeneration.
      Title: Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models.
    6. these findings indicate that DLK participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins.
      Title: Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrest.
    7. The results confirm the significance of apoptosis deregulation in CLL, and suggest a possible relationship between ZIPK expression and the clinical course of the disease.
      Title: Assessment of the pathway of apoptosis involving PAR-4, DAXX and ZIPK proteins in CLL patients and its relationship with the principal prognostic factors.
    8. the DLK-ERK signaling pathway may act as a regulator of the interaction that occurs between Hsp27 and the cytoskeleton during the formation of the cornified cell envelope, a process conferring to the skin its crucial barrier function
      Title: The small heat-shock protein Hsp27 undergoes ERK-dependent phosphorylation and redistribution to the cytoskeleton in response to dual leucine zipper-bearing kinase expression.
    9. Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator)
      Title: Genetic variation in MicroRNA genes and risk of oral premalignant lesions.
    10. Observational study of gene-disease association. (HuGE Navigator)
      Title: The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.
    Submit: New GeneRIF Correction See all GeneRIFs (15)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables JUN kinase kinase kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein homodimerization activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables protein kinase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    enables protein kinase binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein serine/threonine kinase activator activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables protein serine/threonine kinase activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in JNK cascade ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    involved_in intracellular signal transduction TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in negative regulation of motor neuron apoptotic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in peptidyl-serine phosphorylation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in positive regulation of DNA-templated transcription IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in positive regulation of ERK1 and ERK2 cascade IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in positive regulation of JUN kinase activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in positive regulation of protein kinase activity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in post-translational protein modification ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in protein autophosphorylation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in cytoplasm TAS
    Traceable Author Statement
    more info
    		 PubMed 
    located_in cytosol ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in growth cone IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    located_in plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase 12
    Names
    MAPK-upstream kinase
    dual leucine zipper bearing kinase
    dual leucine zipper kinase DLK
    leucine zipper protein kinase
    mixed lineage kinase
    protein kinase MUK
    NP_001180440.1
    NP_006292.3
    XP_005269195.1
    XP_005269197.1
    XP_006719651.1
    XP_011537027.1
    XP_016875445.1
    XP_047285478.1
    XP_047285479.1
    XP_054229158.1
    XP_054229159.1
    XP_054229160.1
    XP_054229161.1
    XP_054229162.1
    XP_054229163.1

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001193511.2 → NP_001180440.1  mitogen-activated protein kinase kinase kinase 12 isoform 1

      See identical proteins and their annotated locations for NP_001180440.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AC023509, AK094195, BC050050
      Consensus CDS
      CCDS55831.1
      UniProtKB/Swiss-Prot
      Q12852
      Related
      ENSP00000449038.1, ENST00000547488.6
      Conserved Domains (2) summary
      smart00219
      Location:165 → 397
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:164 → 400
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    2. NM_006301.4 → NP_006292.3  mitogen-activated protein kinase kinase kinase 12 isoform 2

      See identical proteins and their annotated locations for NP_006292.3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region compared to variant 1. The resulting protein (isoform 2) is shorter but has the same N- and C-termini compared to isoform 1.
      Source sequence(s)
      AC023509, AK094195, U07358
      Consensus CDS
      CCDS8860.1
      UniProtKB/Swiss-Prot
      B3KSS9, G3V1Y2, Q12852, Q86VQ5, Q8WY25
      Related
      ENSP00000267079.2, ENST00000267079.6
      Conserved Domains (2) summary
      smart00219
      Location:132 → 364
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:131 → 367
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000012.12 Reference GRCh38.p14 Primary Assembly

      Range
      53479669..53501539 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011538725.4 → XP_011537027.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

      See identical proteins and their annotated locations for XP_011537027.1

      UniProtKB/Swiss-Prot
      Q12852
      Conserved Domains (2) summary
      smart00219
      Location:165 → 397
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:164 → 400
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    2. XM_005269138.5 → XP_005269195.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

      See identical proteins and their annotated locations for XP_005269195.1

      UniProtKB/Swiss-Prot
      Q12852
      Related
      ENSP00000448689.1, ENST00000547035.5
      Conserved Domains (2) summary
      smart00219
      Location:165 → 397
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:164 → 400
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    3. XM_017019956.3 → XP_016875445.1  mitogen-activated protein kinase kinase kinase 12 isoform X2

      UniProtKB/Swiss-Prot
      B3KSS9, G3V1Y2, Q12852, Q86VQ5, Q8WY25
      Conserved Domains (2) summary
      smart00219
      Location:132 → 364
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:131 → 367
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    4. XM_006719588.5 → XP_006719651.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

      See identical proteins and their annotated locations for XP_006719651.1

      UniProtKB/Swiss-Prot
      Q12852
      Conserved Domains (2) summary
      smart00219
      Location:165 → 397
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:164 → 400
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    5. XM_047429523.1 → XP_047285479.1  mitogen-activated protein kinase kinase kinase 12 isoform X4

    6. XM_047429522.1 → XP_047285478.1  mitogen-activated protein kinase kinase kinase 12 isoform X3

    7. XM_005269140.3 → XP_005269197.1  mitogen-activated protein kinase kinase kinase 12 isoform X5

      UniProtKB/TrEMBL
      F8VUG4
      Related
      ENSP00000447889.1, ENST00000552365.1
      Conserved Domains (2) summary
      smart00219
      Location:165 → 397
      TyrKc; Tyrosine kinase, catalytic domain
      cd14059
      Location:164 → 400
      STKc_MAP3K12_13; Catalytic domain of the Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinases 12 and 13

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060936.1 Alternate T2T-CHM13v2.0

      Range
      53445716..53466177 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054373184.1 → XP_054229159.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

    2. XM_054373183.1 → XP_054229158.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

    3. XM_054373186.1 → XP_054229161.1  mitogen-activated protein kinase kinase kinase 12 isoform X2

      UniProtKB/Swiss-Prot
      B3KSS9, G3V1Y2, Q12852, Q86VQ5, Q8WY25

    4. XM_054373185.1 → XP_054229160.1  mitogen-activated protein kinase kinase kinase 12 isoform X1

    5. XM_054373187.1 → XP_054229162.1  mitogen-activated protein kinase kinase kinase 12 isoform X4

    6. XM_054373188.1 → XP_054229163.1  mitogen-activated protein kinase kinase kinase 12 isoform X5

      UniProtKB/TrEMBL
      F8VUG4
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q12852.2 GenPept UniProtKB/Swiss-Prot:Q12852

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