TBC1D3

Summary

TBC1D3 (TBC1 domain family member 3, HGNC:19031) is a protein-coding gene on chromosome 17q12, encoding TBC1 domain family member 3 (Q8IZP1). Acts as a GTPase activating protein for RAB5.

Predicted to enable GTPase activator activity. Predicted to be located in early endosome membrane.

Source: NCBI Gene 729873 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 5 total
• MANE Select transcript: NM_001123391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19031
Approved symbol	TBC1D3
Name	TBC1 domain family member 3
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	TBC1D3A, DKFZp434P2235, PRC17
Ensembl gene	ENSG00000274611
Ensembl biotype	protein_coding
OMIM	607741
Entrez	729873

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000620215, ENST00000896521

RefSeq mRNA: 1 — MANE Select: NM_001123391 NM_001123391

CCDS: CCDS45658

Canonical transcript exons

ENST00000617279 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 113 present calls, max score 86.05.

Top tissues by expression

133 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	86.05	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.60	silver quality
sural nerve	UBERON:0015488	70.75	gold quality
colonic epithelium	UBERON:0000397	55.26	silver quality
fundus of stomach	UBERON:0001160	50.20	gold quality
granulocyte	CL:0000094	50.15	silver quality
left testis	UBERON:0004533	48.35	gold quality
testis	UBERON:0000473	47.91	gold quality
right adrenal gland cortex	UBERON:0035827	45.96	gold quality
skeletal muscle tissue	UBERON:0001134	45.87	silver quality
bone marrow cell	CL:0002092	45.65	silver quality
lymph node	UBERON:0000029	45.40	gold quality
right ovary	UBERON:0002118	42.84	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	42.29	gold quality
muscle tissue	UBERON:0002385	42.14	silver quality
right testis	UBERON:0004534	41.53	gold quality
ganglionic eminence	UBERON:0004023	40.31	gold quality
rectum	UBERON:0001052	40.04	gold quality
blood	UBERON:0000178	39.12	gold quality
liver	UBERON:0002107	39.09	gold quality
adenohypophysis	UBERON:0002196	39.02	gold quality
right adrenal gland	UBERON:0001233	38.91	gold quality
bone marrow	UBERON:0002371	38.81	gold quality
gall bladder	UBERON:0002110	38.76	gold quality
ectocervix	UBERON:0012249	37.71	gold quality
left adrenal gland cortex	UBERON:0035825	36.69	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
tonsil	UBERON:0002372	35.81	silver quality
urinary bladder	UBERON:0001255	34.75	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting TBC1D3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-3940-5P	99.14	65.26	493
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-455-5P	98.74	67.31	795

Literature-anchored findings (GeneRIF, showing 10)

• We describe eight highly related TBC1D3 paralogues located on Chromosome 17q12 that display specific transcription patterns in human tissues, and that pattern is altered in several primary prostate tumors in comparison to healthy prostate tissues. (PMID:16863688)
• Altered growth factor receptor trafficking and GTP-Ras turnover may be sites where recently evolved genes such as TBC1D3 selectively modulate signaling in hominoids and humans (PMID:18319245)
• TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling (PMID:22348058)
• Growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8. (PMID:23029530)
• TBC1D3 is targeted to the plasma membrane by protein palmitoylation. (PMID:23578663)
• these studies indicate a novel model by which the microtubule network regulates EGFR stability and signaling through tubulin dimer/oligomer interaction with the nucleocytoplasmic protein TBC1D3. (PMID:24714105)
• Here, the found that expression of TBC1D3 in ventricular cortical progenitors of mice via in utero electroporation caused delamination of ventricular radial glia cells (vRGs) and promoted generation of self-renewing basal progenitors with typical morphology of outer radial glia (oRG), which are most abundant in primates. Expression of TBC1D3, was often found to underlie cortical regions exhibiting folding. (PMID:27504805)
• our work reveals a novel model by which CaM promotes cell migration through inhibiting the ubiquitination and degradation of TBC1D3. (PMID:28422741)
• High TBC1B3 expression is associated with breast cancer. (PMID:28844714)
• TBC1D3 promotes neural progenitor proliferation by suppressing the histone methyltransferase G9a. (PMID:33523893)

Cross-species orthologs

0 orthologs

Paralogs (45): RABGAP1 (ENSG00000011454), TBC1D22A (ENSG00000054611), TBC1D22B (ENSG00000065491), TBC1D1 (ENSG00000065882), EVI5 (ENSG00000067208), TBC1D25 (ENSG00000068354), TBC1D2 (ENSG00000095383), TBC1D10A (ENSG00000099992), SGSM3 (ENSG00000100359), TBC1D17 (ENSG00000104946), TBC1D13 (ENSG00000107021), TBC1D12 (ENSG00000108239), TBC1D9 (ENSG00000109436), TBC1D30 (ENSG00000111490), TBC1D15 (ENSG00000121749), TBC1D5 (ENSG00000131374), TBC1D14 (ENSG00000132405), TBC1D8B (ENSG00000133138), TBC1D4 (ENSG00000136111), GRTP1 (ENSG00000139835), SGSM2 (ENSG00000141258), EVI5L (ENSG00000142459), TBCK (ENSG00000145348), USP6NL (ENSG00000148429), RABGAP1L (ENSG00000152061), SGSM1 (ENSG00000167037), TBC1D21 (ENSG00000167139), TBC1D2B (ENSG00000167202), TBC1D16 (ENSG00000167291), TBC1D10B (ENSG00000169221), TBC1D10C (ENSG00000175463), TBC1D28 (ENSG00000189375), TBC1D9B (ENSG00000197226), TBC1D8 (ENSG00000204634), TBC1D26 (ENSG00000214946), TBC1D3G (ENSG00000260287), TBC1D3K (ENSG00000273513), TBC1D3H (ENSG00000274226), TBC1D3D (ENSG00000274419), TBC1D3L (ENSG00000274512)

Protein

Protein identifiers

TBC1 domain family member 3 — Q8IZP1 (reviewed: Q8IZP1)

Alternative names: Prostate cancer gene 17 protein, Protein TRE17-alpha, Rab GTPase-activating protein PRC17

All UniProt accessions (1): Q8IZP1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a GTPase activating protein for RAB5. Does not act on RAB4 or RAB11.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in liver, skeletal muscle, kidney, pancreas, spleen, testis, ovary, small intestine and peripheral blood leukocytes. Overexpressed in prostate cancers.

Post-translational modifications. Ubiquitinated by a CUL7-based E3 ligase, which leads to proteasomal degradation. Palmitoylation is required for membrane localization and protects TBC1D3 from ubiquitination.

Miscellaneous. TBC1D3 is encoded by a collection of very similar paralogs with multiple copies of each paralog, some human genomes encoding well over 50 copies depending on ethnic origin of the donor.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZP1-1	1	yes
Q8IZP1-2	2

RefSeq proteins (1): NP_001116863* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000195	Rab-GAP-TBC_dom	Domain
IPR035969	Rab-GAP_TBC_sf	Homologous_superfamily
IPR050302	Rab_GAP_TBC_domain	Family

Pfam: PF00566

UniProt features (14 total): sequence conflict 5, lipid moiety-binding region 2, splice variant 2, chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZP1-F1	60.64	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 318, 325

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8854214	TBC/RABGAPs
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport
R-HSA-9007101	Rab regulation of trafficking

MSigDB gene sets: 41 (showing top): REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CILIUM_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_REGULATION_OF_CILIUM_ASSEMBLY, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_REGULATION_OF_CELL_PROJECTION_ASSEMBLY, GOBP_REGULATION_OF_ORGANELLE_ASSEMBLY, GOCC_EARLY_ENDOSOME_MEMBRANE, GOMF_ENZYME_ACTIVATOR_ACTIVITY, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, REACTOME_VESICLE_MEDIATED_TRANSPORT, REACTOME_TBC_RABGAPS

GO Biological Process (0):

GO Molecular Function (1): GTPase activator activity (GO:0005096)

GO Cellular Component (4): plasma membrane (GO:0005886), early endosome membrane (GO:0031901), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Rab regulation of trafficking	1
Vesicle-mediated transport	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
membrane	1
cell periphery	1
early endosome	1
endosome membrane	1
endomembrane system	1
cytoplasmic vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

222 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBC1D3	USP32	Q8NFA0	916
TBC1D3	OR4X2	Q8NGF9	507
TBC1D3	TBC1D30	Q9Y2I9	353
TBC1D3	BLTP2	Q14667	348
TBC1D3	GEMIN8	Q9NWZ8	336
TBC1D3	NPIPA3	F8WFD2	321
TBC1D3	CDC16	Q13042	303
TBC1D3	ADGRG4	Q8IZF6	300
TBC1D3	SLC6A18	Q96N87	294
TBC1D3	PCDHA11	Q9Y5I1	289
TBC1D3	PCDHA12	Q9UN75	288
TBC1D3	CUL7	Q14999	284
TBC1D3	PCDHA10	Q9Y5I2	279
TBC1D3	PCDHA5	Q9Y5H7	274
TBC1D3	PCDHA8	Q9Y5H6	272

IntAct

4 interactions, top by confidence:

A	B	Type	Score
M		psi-mi:“MI:0914”(association)	0.350
TBC1D3	smC	psi-mi:“MI:0915”(physical association)	0.000
TBC1D3	YWHAE	psi-mi:“MI:0915”(physical association)	0.000

ESM2 similar proteins: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A6NDS4, A6NER0, A6QPT6, B9A6J9, M3WHG5, O14771, O15482, O15553, O19110, O76081, P0C7X1, P0C7X3, P0C7X4, P35125, P48778, P48967, P79209, Q13670, Q15697, Q2TBC4, Q3T191, Q3UZD7, Q4R2Z8, Q5DRQ5, Q5SSQ6, Q5XFX8, Q69ZB3, Q6DHY5, Q6IPX1, Q6ZMN8, Q8BLR5, Q8BWA8, Q8IYF1, Q8IZP1, Q8JZW5, Q8N7G0

Diamond homologs: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A2AWA9, A6H6A9, A6NDS4, A6NER0, B9A6J9, H2KZZ6, P0C7X1, P35125, Q2M2D7, Q5RAN1, Q5SVR0, Q66K14, Q6DHY5, Q6IPX1, Q80XC3, Q86UD7, Q8IZP1, Q92738, Q9UFV1, Q9Y3P9, A3KGB4, A6QP29, B0R0W9, B7ZAP0, O60343, O60447, O95759, O97790, P58802, P97366, Q0IIM8, Q10496, Q12317, Q12344, Q28CB1, Q3UYK3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

5 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000628244 (17:38193594 G>A), RS1041404958 (17:38190467 G>T), RS111923767 (17:38193528 C>T), RS1156238405 (17:38192689 C>T), RS1159319082 (17:38192073 G>A), RS1159386369 (17:38186750 C>T), RS1159463111 (17:38193873 G>A), RS1159971675 (17:38184020 G>T), RS1160846265 (17:38188275 G>T), RS1160879688 (17:38187322 G>A), RS1161706015 (17:38183562 T>C), RS1162010052 (17:38186882 C>G), RS1162447251 (17:38185008 G>A), RS1162819175 (17:38184106 A>G), RS1162993178 (17:38194327 GGAGAA>G)

Disease associations

OMIM: gene MIM:607741 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001941_16	Ovarian cancer	8.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Amiodarone	increases expression	1
Arsenic	decreases expression, increases abundance	1
Cadmium	decreases expression	1
Manganese	decreases expression, increases abundance	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	decreases expression	1
Cyclosporine	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.