TBC1D4 Gene
TBC1 Domain Family Member 4: A Key Regulator of Insulin Signaling and Glucose Metabolism
Gene Information Card
| Symbol | TBC1D4 |
|---|---|
| Full Name | TBC1 Domain Family Member 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 13q22.2 |
| NCBI Gene ID | 9882 ncbi.nlm.nih.gov/gene/9882 |
| Ensembl ID | ENSG00000136156 |
| UniProt ID | O60343 |
| OMIM ID | 612465 |
| HGNC ID | 19170 |
| Aliases | AS160, KIAA0603, FLJ20731 |
Description
TBC1D4 encodes a Rab GTPase-activating protein (RabGAP) that is a key substrate of Akt (PKB). It regulates insulin-stimulated glucose uptake by controlling the translocation of GLUT4-containing vesicles to the plasma membrane in muscle and adipose tissue. Phosphorylation of TBC1D4 by Akt inactivates its GAP activity, allowing Rab proteins to promote GLUT4 exocytosis. Loss-of-function variants are associated with postprandial hyperinsulinemia and increased risk of type 2 diabetes.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Type 2 Diabetes | Impaired insulin-stimulated GLUT4 translocation due to reduced TBC1D4 phosphorylation or expression | GWAS and functional studies (PMID: 21768215, 21873549) |
| Postprandial Hyperinsulinemia | Defective TBC1D4-mediated Rab inactivation leads to delayed glucose clearance | Family-based studies (PMID: 24699462) |
| Obesity | Altered TBC1D4 expression in adipose tissue contributes to insulin resistance | Expression analysis (PMID: 19074966) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal Muscle | 10.2 | Medium |
| Adipose Tissue | 8.5 | Medium |
| Heart | 6.1 | Low |
| Liver | 2.3 | Low |
| Pancreas | 1.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 5.4 | Moderate expression |
| HepG2 | 3.2 | Low expression |
| C2C12 (myotubes) | 12.1 | High expression |
| 3T3-L1 (adipocytes) | 9.8 | High expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg363* | Nonsense | <0.01% | Premature stop; loss of RabGAP domain; associated with hyperinsulinemia |
| p.Arg1250Trp | Missense | 0.02% | Reduced Akt phosphorylation site; impaired GLUT4 translocation |
| p.Thr642Ala | Missense | 0.01% | Altered phosphorylation; decreased insulin sensitivity |
Mutation functional classification
Loss of Function (LOF)
Nonsense and frameshift mutations that truncate the RabGAP domain (e.g., p.Arg363*) lead to loss of GAP activity and impaired GLUT4 translocation.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported.
Dominant Negative (DN)
Missense mutations at key phosphorylation sites (e.g., p.Thr642Ala) may act dominant-negatively by competing with wild-type TBC1D4 for Akt binding.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Insulin signaling pathway (KEGG: hsa04910)
• Regulation of GLUT4 translocation (Reactome: R-HSA-1445148)
• Akt-mediated inactivation of TBC1D4 (Reactome: R-HSA-199991)
Protein Summary
TBC1D4 (AS160) is a 1299-amino-acid Rab GTPase-activating protein containing a RabGAP domain and multiple Akt phosphorylation sites. It is predominantly expressed in insulin-sensitive tissues such as skeletal muscle and adipose tissue. Upon insulin stimulation, Akt phosphorylates TBC1D4, inhibiting its GAP activity and allowing Rab proteins (e.g., Rab10, Rab14) to facilitate GLUT4 vesicle translocation to the plasma membrane. This process is critical for postprandial glucose uptake. Dysregulation of TBC1D4 contributes to insulin resistance and type 2 diabetes.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TBC1D4 Knockout HEK293 Cell Line | EDJ-KQ6802 | Human | 9882 | Details Get a Quote |
| TBC1D4 Knockout A-549 Cell Line | EDJ-KQ31299 | Human | 9882 | Details Get a Quote |
| TBC1D4 Knockout HCT 116 Cell Line | EDJ-KQ31300 | Human | 9882 | Details Get a Quote |
| TBC1D4 Knockout HeLa Cell Line | EDJ-KQ31301 | Human | 9882 | Details Get a Quote |
