TBC1D1: TBC1 Domain Family Member 1

A Rab-GTPase activating protein implicated in insulin signaling, glucose metabolism, and obesity risk.

Gene Information Card

Symbol TBC1D1
Full Name TBC1 domain family member 1
Gene Type protein-coding
Chromosomal Location 4q24
NCBI Gene ID 23216 ncbi.nlm.nih.gov/gene/23216
Ensembl ID ENSG00000138669
UniProt ID Q86TI0
OMIM ID 609850
HGNC ID 28978
Aliases KIAA1108, TBC1, TBC1D1

Description

TBC1D1 encodes a member of the TBC (Tre-2/Bub2/Cdc16) domain-containing family of Rab-GTPase activating proteins (Rab-GAPs). The protein functions as a negative regulator of Rab proteins involved in intracellular vesicle trafficking, particularly GLUT4 translocation in response to insulin. TBC1D1 is phosphorylated by AMPK and Akt, modulating its GAP activity and thereby influencing glucose uptake. Genetic variation in TBC1D1 has been associated with obesity, insulin resistance, and type 2 diabetes.

Disease Associations

Disease category Pathophysiological mechanism Genomic evidence
Obesity Loss-of-function variants impair Rab-GAP activity, leading to altered GLUT4 trafficking and increased adiposity. Association studies (PMID: 18327255, 19079258)
Type 2 diabetes Impaired insulin-stimulated glucose uptake due to defective TBC1D1 regulation. GWAS and candidate gene studies (PMID: 19079258, 21512144)
Insulin resistance Dysregulation of TBC1D1 phosphorylation and Rab-GAP activity contributes to reduced insulin sensitivity. Functional studies in muscle and adipose tissue (PMID: 21512144)

Expression Profile

Tissue Expression
Tissue nTPM level
Skeletal muscle 12.5 Medium
Heart 9.8 Medium
Adipose tissue 7.2 Low
Brain 5.1 Low
Liver 2.3 Not detected
Cell Line Expression
Cell Line nTPM Notes
HeLa 8.4 Moderate expression
HepG2 6.1 Low expression
C2C12 (myotubes) 15.2 High expression
3T3-L1 (adipocytes) 9.7 Medium expression
Data source：Human Protein Atlas（proteinatlas.org）

Mutations & Variants

Hotspot Mutations
Variant Type Frequency Functional Description
p.Arg125Trp (rs6817820) Missense ~5% in European populations Reduced GAP activity, associated with obesity
p.Arg125Gln (rs6817821) Missense ~2% in European populations Impaired insulin-stimulated GLUT4 translocation
p.Leu541Pro (rs35859249) Missense <1% Unknown functional effect
Mutation functional classification

Loss of Function (LOF)

p.Arg125Trp and p.Arg125Gln reduce Rab-GAP activity, impairing GLUT4 translocation and promoting obesity.

Gain of Function (GOF)

No gain-of-function variants reported in TBC1D1.

Dominant Negative (DN)

Not described for TBC1D1.
View complete mutation data：
ClinVar：https://www.clinvar.com/gene/23216
COSMIC：https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=TBC1D1

Gene Ontology (GO)

• GTPase activator activity (GO:0005096) • protein binding (GO:0005515)
• endosome (GO:0005768) • cytosol (GO:0005829)
• positive regulation of gene expression (GO:0010628) • cellular response to insulin stimulus (GO:0032869)
• positive regulation of glucose import (GO:0046326) • regulation of mitotic cell cycle phase transition (GO:1901990)

Pathways

• Insulin signaling pathway (Reactome: R-HSA-74752)
• GLUT4 translocation (Reactome: R-HSA-1445148)
• AMPK signaling (Reactome: R-HSA-380972)

Protein Summary

TBC1D1 is a 1168-amino acid protein containing a TBC domain (Rab-GAP) and multiple phosphorylation sites for AMPK and Akt. It localizes to endosomal compartments and regulates the GTPase activity of Rab proteins (e.g., Rab8A, Rab10, Rab14) involved in GLUT4 vesicle trafficking. Phosphorylation by AMPK at Ser237 and by Akt at Thr596 modulates its GAP activity, linking energy status and insulin signaling to glucose uptake. Structural studies reveal a dimeric organization and a conserved catalytic arginine finger in the TBC domain.

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Related Products

Product name Cat.No. Species Gene ID
TBC1D1 Knockout HEK293 Cell Line EDJ-KQ1879 Human 23216 Details Get a Quote
TBC1D12 Knockout HEK293 Cell Line EDJ-KQ7901 Human 23232 Details Get a Quote
TBC1D16 Knockout HEK293 Cell Line EDJ-KQ7974 Human 125058 Details Get a Quote
TBC1D10B Knockout HEK293 Cell Line EDJ-KQ8348 Human 26000 Details Get a Quote
TBC1D10A Knockout HEK293 Cell Line EDJ-KQ9914 Human 83874 Details Get a Quote
TBC1D13 Knockout HEK293 Cell Line EDJ-KQ11477 Human 54662 Details Get a Quote
TBC1D15 Knockout HEK293 Cell Line EDJ-KQ11933 Human 64786 Details Get a Quote
TBC1D10C Knockout HEK293 Cell Line EDJ-KQ15644 Human 374403 Details Get a Quote
TBC1D14 Knockout HEK293 Cell Line EDJ-KQ15645 Human 57533 Details Get a Quote
TBC1D17 Knockout HEK293 Cell Line EDJ-KQ15646 Human 79735 Details Get a Quote
TBC1D19 Knockout HEK293 Cell Line EDJ-KQ15648 Human 55296 Details Get a Quote
TBC1D12 Knockout HeLa Cell Line EDJ-KQ32179 Human 23232 Details Get a Quote
TBC1D16 Knockout A-549 Cell Line EDJ-KQ34940 Human 125058 Details Get a Quote
TBC1D16 Knockout HCT 116 Cell Line EDJ-KQ34942 Human 125058 Details Get a Quote
TBC1D16 Knockout HeLa Cell Line EDJ-KQ34943 Human 125058 Details Get a Quote

Reference Databases

NCBI Gene https://www.ncbi.nlm.nih.gov/gene/23216
OMIM https://www.omim.org/entry/609850
HGNC https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:28978
Ensembl https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138669
UniProt https://www.uniprot.org/uniprot/Q86TI0
ClinVar https://www.ncbi.nlm.nih.gov/clinvar/?term=TBC1D1%5Bgene%5D
COSMIC https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=TBC1D1
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