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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
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Genomic context

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See TBC1D4 in Genome Data Viewer
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
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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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