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    TBC1D4 TBC1 domain family member 4 [ Homo sapiens (human) ]

    Gene ID: 9882, updated on 3-Apr-2024

    Summary

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    Official Symbol
    TBC1D4provided by HGNC
    Official Full Name
    TBC1 domain family member 4provided by HGNC
    Primary source
    HGNC:HGNC:19165
    See related
    Ensembl:ENSG00000136111 MIM:612465; AllianceGenome:HGNC:19165
    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
    AS160; NIDDM5
    Summary
    This gene is a member of the Tre-2/BUB2/CDC16 domain family. The protein encoded by this gene is a Rab-GTPase-activating protein, and contains two phopshotyrosine-binding domains (PTB1 and PTB2), a calmodulin-binding domain (CBD), a Rab-GTPase domain, and multiple AKT phosphomotifs. This protein is thought to play an important role in glucose homeostasis by regulating the insulin-dependent trafficking of the glucose transporter 4 (GLUT4), important for removing glucose from the bloodstream into skeletal muscle and fat tissues. Reduced expression of this gene results in an increase in GLUT4 levels at the plasma membrane, suggesting that this protein is important in intracellular retention of GLUT4 under basal conditions. When exposed to insulin, this protein is phosphorylated, dissociates from GLUT4 vesicles, resulting in increased GLUT4 at the cell surface, and enhanced glucose transport. Phosphorylation of this protein by AKT is required for proper translocation of GLUT4 to the cell surface. Individuals homozygous for a mutation in this gene are at higher risk for type 2 diabetes and have higher levels of circulating glucose and insulin levels after glucose ingestion. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
    Expression
    Ubiquitous expression in adrenal (RPKM 28.9), ovary (RPKM 15.3) and 23 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    13q22.2
    Exon count:
    23
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 13 NC_000013.11 (75283503..75482169, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 13 NC_060937.1 (74507182..74705799, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 13 NC_000013.10 (75857639..76056305, complement)

    Chromosome 13 - NC_000013.11Genomic Context describing neighboring genes Neighboring gene long intergenic non-protein coding RNA 1078 Neighboring gene CTAGE family member 11, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7821 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr13:75899800-75900999 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7822 Neighboring gene Sharpr-MPRA regulatory region 11619 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr13:75935886-75936406 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7823 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7824 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7825 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7826 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5401 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 5402 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7827 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7828 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7829 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7830 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 7831 Neighboring gene H3K27ac hESC enhancer GRCh37_chr13:76123825-76124385 Neighboring gene COMM domain containing 6 Neighboring gene ubiquitin C-terminal hydrolase L3 Neighboring gene LMO7 antisense RNA 1

    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. The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland. Overvad M, et al. Int J Circumpolar Health, 2023 Dec. PMID 36944026, Free PMC Article
    2. Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers. Schnurr TM, et al. Diabetologia, 2021 Aug. PMID 33912980, Free PMC Article
    3. The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland. Overvad M, et al. Sci Rep, 2020 Dec 16. PMID 33328529, Free PMC Article
    4. Tankyrase inhibition augments neuronal insulin sensitivity and glucose uptake via AMPK-AS160 mediated pathway. Manglani K, et al. Neurochem Int, 2020 Dec. PMID 33002563
    5. The carboxy-terminal region of the TBC1D4 (AS160) RabGAP mediates protein homodimerization. Woo JR, et al. Int J Biol Macromol, 2017 Oct. PMID 28545963, Free PMC Article

    See all (109) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland.
      Title: The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland.
    2. Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers.
      Title: Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers.
    3. Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes.
      Title: Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes.
    4. Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots?
      Title: Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots?
    5. Tankyrase inhibition augments neuronal insulin sensitivity and glucose uptake via AMPK-AS160 mediated pathway.
      Title: Tankyrase inhibition augments neuronal insulin sensitivity and glucose uptake via AMPK-AS160 mediated pathway.
    6. The long isoform of TBC1D4 is primarily expressed in skeletal muscle. Decreased protein abundance of the long isoform and of the mRNA encoding it in individuals carrying one or two copies of the TBC1D4 p.Arg684Ter allele is correlated with increased plasma glucose levels and increased frequency of T2D.
      Title: A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes.
    7. Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans.
      Title: Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans.
    8. The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland.
      Title: The effect of diabetes and the common diabetogenic TBC1D4 p.Arg684Ter variant on cardiovascular risk in Inuit in Greenland.
    9. WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1
      Title: WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1.
    10. C-terminal region (CTR) region is largely alpha-helical and mediates TBC1D4 RabGAP dimerization
      Title: The carboxy-terminal region of the TBC1D4 (AS160) RabGAP mediates protein homodimerization.
    Submit: New GeneRIF Correction See all GeneRIFs (37)

    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

    Associated conditions

    Description Tests
    Diabetes mellitus, noninsulin-dependent, 5
    MedGen: C4015183 OMIM: 616087 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.
    EBI GWAS Catalog
    Genome-wide association study in a Chinese population with diabetic retinopathy.
    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

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Nef nef HIV-1 Nef decreases levels of AS160 phosphorylation in insulin-stimulated adipocytes PubMed

    Go to the HIV-1, Human Interaction Database

    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

    Clone Names

    • DKFZp779C0666

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables GTPase activator activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in activation of GTPase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in cellular response to insulin stimulus IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in negative regulation of vesicle fusion IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in vesicle-mediated transport IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
    		  
    located_in vesicle IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    TBC1 domain family member 4
    Names
    TBC (Tre-2, BUB2, CDC16) domain-containing protein
    akt substrate of 160 kDa

    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_042850.1 RefSeqGene

      Range
      5000..203666
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001286658.2 → NP_001273587.1  TBC1 domain family member 4 isoform 2

      See identical proteins and their annotated locations for NP_001273587.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate in-frame exon in the central coding region, compared to variant 1. The encoded isoform (2) is shorter than isoform 1.
      Source sequence(s)
      AB011175, AK307493, AL139230, AL162571, CA448893, FM207107
      Consensus CDS
      CCDS66564.1
      UniProtKB/TrEMBL
      A0A3B3IRT3
      Related
      ENSP00000395986.2, ENST00000431480.6
      Conserved Domains (5) summary
      smart00164
      Location:910 → 1124
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      smart00462
      Location:31 → 190
      PTB; Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain
      cd01269
      Location:193 → 437
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:798 → 856
      DUF3350; Domain of unknown function (DUF3350)
      pfam13094
      Location:1191 → 1262
      CENP-Q; CENP-Q, a CENPA-CAD centromere complex subunit

    2. NM_001286659.2 → NP_001273588.1  TBC1 domain family member 4 isoform 3

      See identical proteins and their annotated locations for NP_001273588.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3, also known as AS160_v2, PMID:18771725) lacks two alternate in-frame exons in the central coding region, compared to variant 1. The encoded isoform (3) is shorter than isoform 1.
      Source sequence(s)
      AB011175, AK307493, AL139230, AL162571, CA448893, FM207106
      Consensus CDS
      CCDS66563.1
      UniProtKB/TrEMBL
      A0A3B3IRT3
      Related
      ENSP00000366852.2, ENST00000377625.6
      Conserved Domains (5) summary
      smart00164
      Location:855 → 1069
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      smart00462
      Location:31 → 190
      PTB; Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain
      cd01269
      Location:193 → 437
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:743 → 801
      DUF3350; Domain of unknown function (DUF3350)
      pfam13094
      Location:1136 → 1207
      CENP-Q; CENP-Q, a CENPA-CAD centromere complex subunit

    3. NM_014832.5 → NP_055647.2  TBC1 domain family member 4 isoform 1

      See identical proteins and their annotated locations for NP_055647.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AB011175, AK307493, AL139230, AL162571, CA448893, FM207106
      Consensus CDS
      CCDS41901.1
      UniProtKB/Swiss-Prot
      A7E2X8, B4DU25, B4E235, B6ETN8, B6ETN9, O60343, Q5W0B9, Q68D14
      UniProtKB/TrEMBL
      A0A3B3IRT3
      Related
      ENSP00000366863.3, ENST00000377636.8
      Conserved Domains (5) summary
      smart00164
      Location:918 → 1132
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      smart00462
      Location:31 → 190
      PTB; Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain
      cd01269
      Location:193 → 437
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:806 → 864
      DUF3350; Domain of unknown function (DUF3350)
      pfam13094
      Location:1199 → 1270
      CENP-Q; CENP-Q, a CENPA-CAD centromere complex subunit

    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_000013.11 Reference GRCh38.p14 Primary Assembly

      Range
      75283503..75482169 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047430811.1 → XP_047286767.1  TBC1 domain family member 4 isoform X6

    2. XM_047430810.1 → XP_047286766.1  TBC1 domain family member 4 isoform X5

    3. XM_011535331.3 → XP_011533633.1  TBC1 domain family member 4 isoform X3

      UniProtKB/TrEMBL
      A0A3B3IRT3
      Conserved Domains (5) summary
      smart00164
      Location:881 → 1095
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      smart00462
      Location:31 → 190
      PTB; Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain
      cd01269
      Location:193 → 437
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:769 → 827
      DUF3350; Domain of unknown function (DUF3350)
      pfam13094
      Location:1162 → 1233
      CENP-Q; CENP-Q, a CENPA-CAD centromere complex subunit

    4. XM_047430809.1 → XP_047286765.1  TBC1 domain family member 4 isoform X4

      Related
      ENSP00000496983.1, ENST00000648194.1

    5. XM_047430808.1 → XP_047286764.1  TBC1 domain family member 4 isoform X2

    6. XM_005266603.3 → XP_005266660.1  TBC1 domain family member 4 isoform X1

      UniProtKB/TrEMBL
      A0A3B3IRT3
      Conserved Domains (5) summary
      smart00164
      Location:893 → 1107
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      smart00462
      Location:31 → 190
      PTB; Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain
      cd01269
      Location:193 → 437
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:781 → 839
      DUF3350; Domain of unknown function (DUF3350)
      pfam13094
      Location:1174 → 1245
      CENP-Q; CENP-Q, a CENPA-CAD centromere complex subunit

    7. XM_006719903.4 → XP_006719966.1  TBC1 domain family member 4 isoform X7

      UniProtKB/TrEMBL
      A0A3B3IRT3
      Conserved Domains (3) summary
      smart00164
      Location:760 → 974
      TBC; Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs
      cd01269
      Location:35 → 279
      PTB_TBC1D1_like; TBC1 domain family member 1 and related proteins Phosphotyrosine-binding (PTB) domain
      pfam11830
      Location:648 → 706
      DUF3350; Domain of unknown function (DUF3350)

    8. XM_047430812.1 → XP_047286768.1  TBC1 domain family member 4 isoform X8

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060937.1 Alternate T2T-CHM13v2.0

      Range
      74507182..74705799 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054375233.1 → XP_054231208.1  TBC1 domain family member 4 isoform X6

    2. XM_054375232.1 → XP_054231207.1  TBC1 domain family member 4 isoform X5

    3. XM_054375230.1 → XP_054231205.1  TBC1 domain family member 4 isoform X3

    4. XM_054375231.1 → XP_054231206.1  TBC1 domain family member 4 isoform X4

    5. XM_054375229.1 → XP_054231204.1  TBC1 domain family member 4 isoform X2

    6. XM_054375228.1 → XP_054231203.1  TBC1 domain family member 4 isoform X1

    7. XM_054375234.1 → XP_054231209.1  TBC1 domain family member 4 isoform X7

    8. XM_054375235.1 → XP_054231210.1  TBC1 domain family member 4 isoform X8

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    O60343.2 GenPept UniProtKB/Swiss-Prot:O60343

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