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

Gene ID: 5871, updated on 17-Mar-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_2023_10 current GRCh38.p14 (GCF_000001405.40) 11 NC_000011.10 (64784918..64803214, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 11 NC_060935.1 (64778226..64796524, complement)
105.20220307 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. 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
  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. Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Pombo CM, et al. Nature, 1995 Oct 26. PMID 7477268
  4. 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
  5. Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). Tan L, et al. J Med Chem, 2015 Jan 8. PMID 25075558, Free PMC Article

See all (29) 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)

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 IDA
Inferred from Direct Assay
more info
 PubMed 
enables MAP kinase kinase kinase kinase activity IBA
Inferred from Biological aspect of Ancestor
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 
Process Evidence Code Pubs
involved_in JNK cascade TAS
Traceable Author Statement
more info
 PubMed 
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 IBA
Inferred from Biological aspect of Ancestor
more info
  
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_2023_10

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

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