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    MAP4K2 mitogen-activated protein kinase kinase kinase kinase 2 [ Homo sapiens (human) ]

    Gene ID: 5871, updated on 10-Dec-2024

    Summary

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    Official Symbol
    MAP4K2provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase kinase 2provided by HGNC
    Primary source
    HGNC:HGNC:6864
    See related
    Ensembl:ENSG00000168067 MIM:603166; AllianceGenome:HGNC:6864
    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
    GCK; BL44; RAB8IP
    Summary
    The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
    Expression
    Broad expression in spleen (RPKM 10.3), lymph node (RPKM 8.4) and 24 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP4K2 in Genome Data Viewer
    Location:
    11q13.1
    Exon count:
    32
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 11 NC_000011.10 (64784918..64803214, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 11 NC_060935.1 (64778226..64796524, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 11 NC_000011.9 (64552390..64570686, complement)

    Chromosome 11 - NC_000011.10Genomic Context describing neighboring genes Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64520964-64521574 Neighboring gene glycogen phosphorylase, muscle associated Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:64525447-64526151 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64526152-64526855 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64526856-64527560 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64527561-64528263 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4909 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4910 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64530587-64531460 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64532334-64533208 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:64533209-64534081 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64534082-64534955 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4914 Neighboring gene splicing factor 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3488 Neighboring gene H3K27ac hESC enhancer GRCh37_chr11:64545791-64546392 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:64557481-64557982 Neighboring gene Sharpr-MPRA regulatory region 11124 Neighboring gene MPRA-validated peak1298 silencer Neighboring gene Sharpr-MPRA regulatory region 2965 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4916 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4917 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3490 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3491 Neighboring gene menin 1 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 4918 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr11:64594480-64594980 Neighboring gene CDC42 binding protein kinase gamma Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64609163-64609975 Neighboring gene Sharpr-MPRA regulatory region 8286 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr11:64610788-64611600 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3492 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3493 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 3494

    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. Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Pombo CM, et al. Nature, 1995 Oct 26. PMID 7477268
    2. Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. Katz P, et al. J Biol Chem, 1994 Jun 17. PMID 7515885
    3. Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Matthews JM, et al. Blood, 2016 Jul 14. PMID 27151888, Free PMC Article
    4. MAP4K2 connects the Hippo pathway to autophagy in response to energy stress. Seo G, et al. Autophagy, 2024 Mar. PMID 37937799, Free PMC Article
    5. Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis. Zhang X, et al. Biochem Biophys Res Commun, 2018 Oct 12. PMID 30217450

    See all (30) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. MAP4K2 connects the Hippo pathway to autophagy in response to energy stress.
      Title: MAP4K2 connects the Hippo pathway to autophagy in response to energy stress.
    2. MAP4K2 was up-regulated and its expression was inversely correlated with collagen expression in the osteoblasts from older donors.
      Title: Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis.
    3. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival.
      Title: Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma.
    4. Data indicate 4-substituted 1H-pyrrolo[2,3-b]pyridines as potent inhibitors against TGFbeta-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2).
      Title: Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2).
    5. Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB.
      Title: Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB.
    6. Data suggest that the Rabin8-Rab8-Sec15 interaction may couple the activation of Rab8 to the recruitment of the Rab8 effector and is involved in the regulation of vesicular trafficking for primary cilium formation.
      Title: A Rab8 guanine nucleotide exchange factor-effector interaction network regulates primary ciliogenesis.
    7. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
      Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
    8. Observational study of gene-disease association. (HuGE Navigator)
      Title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
    9. CCM3 is located on the Golgi apparatus, forming a complex with proteins of the germinal center kinase III (GCKIII) family and GM130, a Golgi-resident protein.
      Title: CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation.
    Submit: New GeneRIF Correction

    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

    EBI GWAS Catalog

    Description
    Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    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 3-phosphoinositide-dependent protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables AMP-activated protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables ATP binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables DNA-dependent protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables MAP kinase kinase kinase kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables Rho-dependent protein serine/threonine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables eukaryotic translation initiation factor 2alpha kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AS1 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AS121 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AT120 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AXS139 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2BS14 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2BS36 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S10 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S28 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S57 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T11 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T3 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T45 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T6 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H4S1 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables mitogen-activated protein kinase kinase kinase binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein 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 activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables ribosomal protein S6 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in JNK cascade TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in chromatin remodeling IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in immune response TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in innate immune response IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in intracellular signal transduction IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in intracellular signal transduction IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of JNK cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of JUN kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in vesicle targeting IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in Golgi membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in basolateral plasma membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    is_active_in cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase kinase 2
    Names
    B lymphocyte serine/threonine protein kinase
    MAPK/ERK kinase kinase kinase 2
    MEK kinase kinase 2
    MEKKK 2
    Rab8 interacting protein
    germinal centre kinase (GC kinase)
    NP_001294919.1
    NP_004570.2

    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.

    Genomic

    1. NG_033040.2 RefSeqGene

      Range
      5000..23296
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001307990.2 → NP_001294919.1  mitogen-activated protein kinase kinase kinase kinase 2 isoform 2

      See identical proteins and their annotated locations for NP_001294919.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) uses an alternate in-frame splice site at an internal exon compared to variant 1. It encodes isoform 2, which is shorter than isoform 1.
      Source sequence(s)
      AP001462, BC047865, BU844790, U07349
      Consensus CDS
      CCDS81582.1
      UniProtKB/Swiss-Prot
      Q12851
      Related
      ENSP00000366567.3, ENST00000377350.7
      Conserved Domains (2) summary
      smart00036
      Location:480 → 792
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      cd06613
      Location:16 → 272
      STKc_MAP4K3_like; Catalytic domain of Mitogen-activated protein kinase kinase kinase kinase (MAP4K) 3-like Serine/Threonine Kinases

    2. NM_004579.5 → NP_004570.2  mitogen-activated protein kinase kinase kinase kinase 2 isoform 1

      See identical proteins and their annotated locations for NP_004570.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AP001462, AW574847, BM458161, BU844790, U07349
      Consensus CDS
      CCDS8082.1
      UniProtKB/Swiss-Prot
      Q12851, Q86VU3
      Related
      ENSP00000294066.2, ENST00000294066.7
      Conserved Domains (3) summary
      smart00036
      Location:488 → 800
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:16 → 272
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06613
      Location:16 → 272
      STKc_MAP4K3_like; Catalytic domain of Mitogen-activated protein kinase kinase kinase kinase (MAP4K) 3-like Serine/Threonine Kinases

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000011.10 Reference GRCh38.p14 Primary Assembly

      Range
      64784918..64803214 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060935.1 Alternate T2T-CHM13v2.0

      Range
      64778226..64796524 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q12851.2 GenPept UniProtKB/Swiss-Prot:Q12851

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

    Chemical Information
    Molecular Biology Databases
    Research Materials
    Tools