TOB2

Summary

TOB2 (transducer of ERBB2, 2, HGNC:11980) is a protein-coding gene on chromosome 22q13.2, encoding Protein Tob2 (Q14106). Anti-proliferative protein inhibits cell cycle progression from the G0/G1 to S phases.

TOB2 belongs to the TOB (see TOB1; MIM 605523)/BTG1 (MIM 109580) family of antiproliferative proteins, which are involved in the regulation of cell cycle progression.

Source: NCBI Gene 10766 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_016272

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11980
Approved symbol	TOB2
Name	transducer of ERBB2, 2
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	TOBL, TOB4, bK223H9, APRO5
Ensembl gene	ENSG00000183864
Ensembl biotype	protein_coding
OMIM	607396
Entrez	10766

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000327492, ENST00000434408, ENST00000901391, ENST00000901392, ENST00000901393, ENST00000901394, ENST00000901395, ENST00000901396, ENST00000901397, ENST00000901398, ENST00000937566, ENST00000937567

RefSeq mRNA: 1 — MANE Select: NM_016272 NM_016272

CCDS: CCDS14015

Canonical transcript exons

ENST00000327492 — 2 exons

Exon	Start	End
ENSE00001318027	41433494	41437407
ENSE00001324827	41446379	41446801

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6066 / max 200.4864, expressed in 1796 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194359	12.8222	1790
194360	1.4932	967
194357	0.1993	85
194358	0.0919	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cranial nerve II	UBERON:0000941	97.92	gold quality
paraflocculus	UBERON:0005351	96.68	gold quality
mucosa of stomach	UBERON:0001199	96.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.02	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.93	gold quality
popliteal artery	UBERON:0002250	95.48	gold quality
tibial artery	UBERON:0007610	95.47	gold quality
gastrocnemius	UBERON:0001388	94.81	gold quality
muscle of leg	UBERON:0001383	94.52	gold quality
blood vessel layer	UBERON:0004797	94.42	gold quality
cerebellar hemisphere	UBERON:0002245	94.16	gold quality
cerebellar cortex	UBERON:0002129	94.12	gold quality
cerebellum	UBERON:0002037	93.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.86	gold quality
muscle organ	UBERON:0001630	93.66	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.65	gold quality
aorta	UBERON:0000947	93.24	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.79	gold quality
vastus lateralis	UBERON:0001379	92.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.55	gold quality
lower esophagus	UBERON:0013473	92.50	gold quality
ventricular zone	UBERON:0003053	92.43	gold quality
body of tongue	UBERON:0011876	92.30	gold quality
quadriceps femoris	UBERON:0001377	92.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.23	gold quality
left uterine tube	UBERON:0001303	92.12	gold quality
left lobe of thyroid gland	UBERON:0001120	92.11	gold quality
coronary artery	UBERON:0001621	91.84	gold quality
thyroid gland	UBERON:0002046	91.82	gold quality
right ovary	UBERON:0002118	91.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7052	no	100.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

219 targeting TOB2, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-4725-3P	99.96	69.53	2520

Literature-anchored findings (GeneRIF, showing 8)

• Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system. the C-terminal regions are necessary and sufficient to control the stabilities of BTG1, BTG2, Tob, and Tob2 proteins. (PMID:12135500)
• TNFalpha is able to transactivate ErbB-2 and use it as an obligatory downstream signaling molecule in the generation of mitogenic signals. (PMID:19760502)
• Haploinsufficiency of the MLL and TOB2 genes in lymphoid malignancy. (PMID:19940862)
• study identifies miR-378-TOB2-cyclin D1 as a functional module to mediate the cross talk between Myc and Ras signaling in cellular transformation (PMID:21242960)
• The antiproliferative and the mRNA deadenylation/decay-promoting effects of TOB1 and TOB2 proteins are linked. (PMID:22252318)
• Results show reduced Tob2 expression in primary hepatocellular Carcinoma cells (HCC) and that dysregulation of miR-362 and Tob2 may contribute to HCC malignancy. (PMID:25649327)
• Tob2 phosphorylation regulates global mRNA turnover to reshape transcriptome and impact cell proliferation. (PMID:32404348)
• MiR-375 promotes human periodontal ligament stem cells proliferation and osteogenic differentiation by targeting transducer of ERBB2, 2. (PMID:32619704)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tob2	ENSMUSG00000048546
rattus_norvegicus	Tob2	ENSRNOG00000050500
drosophila_melanogaster	Tob	FBGN0028397
caenorhabditis_elegans	fog-3	WBGENE00001483
caenorhabditis_elegans	T09B4.6	WBGENE00020380

Paralogs (1): TOB1 (ENSG00000141232)

Protein

Protein identifiers

Protein Tob2 — Q14106 (reviewed: Q14106)

Alternative names: Protein Tob4, Transducer of erbB-2 2

All UniProt accessions (2): Q14106, B0QXZ4

UniProt curated annotations — full annotation on UniProt →

Function. Anti-proliferative protein inhibits cell cycle progression from the G0/G1 to S phases.

Subunit / interactions. Associates with CAF1.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the BTG family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14106-1	1	yes
Q14106-2	2

RefSeq proteins (1): NP_057356* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002087	Anti_prolifrtn	Domain
IPR009818	PAM2_motif	Conserved_site
IPR015676	Tob1/2	Family
IPR036054	BTG-like_sf	Homologous_superfamily

Pfam: PF07145, PF07742

UniProt features (11 total): sequence conflict 3, compositionally biased region 3, region of interest 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14106-F1	66.37	0.36

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 (1): 254

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 276 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GGTGTGT_MIR329, TGCGCANK_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MODULE_493, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, NAGASHIMA_NRG1_SIGNALING_UP, GGGTGGRR_PAX4_03, GGCNKCCATNK_UNKNOWN, MAHAJAN_RESPONSE_TO_IL1A_DN, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS

GO Biological Process (7): female gamete generation (GO:0007292), negative regulation of cell population proliferation (GO:0008285), regulation of gene expression (GO:0010468), osteoclast differentiation (GO:0030316), negative regulation of osteoclast differentiation (GO:0045671), positive regulation of ossification (GO:0045778), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (3): transcription corepressor activity (GO:0003714), nuclear vitamin D receptor binding (GO:0042809), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
gamete generation	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
myeloid leukocyte differentiation	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
ossification	1
regulation of ossification	1
positive regulation of multicellular organismal process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
nuclear receptor binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOB2	CNOT7	Q9UIV1	792
TOB2	CNOT8	Q9UFF9	675
TOB2	PABPC1	P11940	592
TOB2	ATAD3B	Q5T9A4	572
TOB2	ERBB2	P04626	548
TOB2	DAZAP2	Q15038	528
TOB2	SLAIN1	Q8ND83	490
TOB2	SMAD7	O15105	457
TOB2	HOXB9	P17482	374
TOB2	CPEB3	Q8NE35	320
TOB2	LYSMD3	Q7Z3D4	319
TOB2	PAG1	Q9NWQ8	310
TOB2	BIVM	Q86UB2	299
TOB2	SP7	Q8TDD2	290
TOB2	CLNK	Q7Z7G1	287

IntAct

38 interactions, top by confidence:

A	B	Type	Score
CNOT7	CNOT1	psi-mi:“MI:0914”(association)	0.880
TOB2	CNOT7	psi-mi:“MI:0915”(physical association)	0.830
CNOT7	TOB2	psi-mi:“MI:0915”(physical association)	0.830
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
CNOT11	CNOT1	psi-mi:“MI:0914”(association)	0.770
PABPC1	TOB2	psi-mi:“MI:0407”(direct interaction)	0.660
TOB2	PABPC1	psi-mi:“MI:0914”(association)	0.660
TOB2	PABPC1	psi-mi:“MI:0915”(physical association)	0.660
BHLHE40	TOB2	psi-mi:“MI:0915”(physical association)	0.560
CEP76	TOB2	psi-mi:“MI:0915”(physical association)	0.560
TOB2	CNOT8	psi-mi:“MI:0915”(physical association)	0.560
TOB2	BHLHE40	psi-mi:“MI:0915”(physical association)	0.560
CNOT8	TOB2	psi-mi:“MI:0915”(physical association)	0.560
TOB2	CEP76	psi-mi:“MI:0915”(physical association)	0.560
TOB2	Cnot7	psi-mi:“MI:0915”(physical association)	0.560
RIBC1	CNOT1	psi-mi:“MI:0914”(association)	0.530
Cnot3	CNOT1	psi-mi:“MI:0915”(physical association)	0.400
CPEB3	TOB2	psi-mi:“MI:0915”(physical association)	0.400
CNOT1	IBTK	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
NANOS2	CNOT1	psi-mi:“MI:0914”(association)	0.350
RIBC1	CNOT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (32): TOB2 (Two-hybrid), TOB2 (Two-hybrid), CNOT7 (Two-hybrid), CEP76 (Two-hybrid), PABPC1 (Affinity Capture-Western), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), TOB2 (Affinity Capture-MS), CNOT7 (Two-hybrid), TOB2 (Two-hybrid), CNOT7 (Reconstituted Complex)

ESM2 similar proteins: A2WXR5, A2XTW9, A2Y0Q2, A2Y4R8, A9LMC0, B8ADZ3, B8AMA8, B8B8C5, B8B8I3, B8BJV8, O19132, O81488, P29475, P29476, P58268, P58269, P58270, Q14106, Q27571, Q29498, Q2R837, Q40359, Q567C6, Q5XEM9, Q60DW3, Q61103, Q66650, Q6EPZ2, Q6IEK5, Q6IEN1, Q6YTY3, Q6Z7F4, Q75IR6, Q7F2Z1, Q7XUW3, Q84TV4, Q8H383, Q8LA16, Q8S8M9, Q8UVR5

Diamond homologs: A4UTQ2, O70552, O88677, P27049, P34743, P40744, P40745, P50615, P50616, P53348, P62324, P62325, P78543, Q04211, Q14106, Q14201, Q54NU5, Q61471, Q63073, Q8R5K6, Q9JM55, Q9NY30

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TOB2	“down-regulates activity”	“CCR4-NOT complex”	binding
CDK1	“up-regulates activity”	TOB2	phosphorylation
CDK2	“up-regulates activity”	TOB2	phosphorylation
CDK4	“up-regulates activity”	TOB2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	6	259.6×	3e-13
Deadenylation of mRNA	7	256.2×	4e-15
M-decay: degradation of maternal mRNAs by maternally stored factors	7	190.3×	2e-14

GO biological processes:

GO term	Partners	Fold	FDR
nuclear-transcribed mRNA poly(A) tail shortening	6	283.2×	2e-12
regulatory ncRNA-mediated gene silencing	5	198.3×	1e-09
regulation of translation	5	64.4×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

378 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41446377:A:AC	donor_gain	1.0000
22:41446378:C:CC	donor_gain	1.0000
22:41446373:A:AC	donor_gain	0.9900
22:41446374:C:CC	donor_gain	0.9900
22:41446374:CT:C	donor_gain	0.9900
22:41446374:CTCA:C	donor_gain	0.9900
22:41446378:CT:C	donor_gain	0.9900
22:41437426:C:CT	acceptor_gain	0.9600
22:41446374:C:CT	donor_loss	0.9600
22:41446375:TCACT:T	donor_loss	0.9600
22:41446376:C:CC	donor_loss	0.9600
22:41446377:A:AT	donor_loss	0.9600
22:41446378:C:CA	donor_loss	0.9600
22:41446378:CTCG:C	donor_gain	0.9600
22:41446372:CACT:C	donor_loss	0.9500
22:41446377:ACT:A	donor_gain	0.9400
22:41446378:CTC:C	donor_gain	0.9400
22:41446404:TC:T	donor_gain	0.9400
22:41437408:C:G	acceptor_gain	0.9300
22:41446373:ACT:A	donor_gain	0.9300
22:41446374:CTC:C	donor_gain	0.9300
22:41446378:CTCGG:C	donor_gain	0.9300
22:41446466:T:A	donor_gain	0.9100
22:41446471:T:A	donor_gain	0.9100
22:41437408:C:CC	acceptor_gain	0.8900
22:41446405:C:CT	donor_gain	0.8900
22:41446406:T:TT	donor_gain	0.8900
22:41446371:TCAC:T	donor_loss	0.8800
22:41437403:CGGCT:C	acceptor_gain	0.8700
22:41437406:CT:C	acceptor_gain	0.8600

AlphaMissense

2258 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:41436786:C:T	G187D	1.000
22:41436788:A:C	F186L	1.000
22:41436788:A:T	F186L	1.000
22:41436789:A:C	F186C	1.000
22:41436789:A:G	F186S	1.000
22:41436790:A:G	F186L	1.000
22:41436793:T:C	K185E	1.000
22:41436795:G:A	T184I	1.000
22:41436801:G:T	A182D	1.000
22:41436803:G:C	F181L	1.000
22:41436803:G:T	F181L	1.000
22:41436804:A:C	F181C	1.000
22:41436804:A:G	F181S	1.000
22:41436805:A:G	F181L	1.000
22:41436926:G:C	F140L	1.000
22:41436926:G:T	F140L	1.000
22:41436928:A:G	F140L	1.000
22:41437011:A:G	L112P	1.000
22:41437011:A:T	L112Q	1.000
22:41437045:A:C	Y101D	1.000
22:41437048:A:G	S100P	1.000
22:41437050:A:T	V99E	1.000
22:41437059:G:T	P96H	1.000
22:41437060:G:A	P96S	1.000
22:41437062:T:C	D95G	1.000
22:41437067:C:A	W93C	1.000
22:41437067:C:G	W93C	1.000
22:41437069:A:G	W93R	1.000
22:41437069:A:T	W93R	1.000
22:41437071:A:T	V92D	1.000

dbSNP variants (sampled 300 via entrez): RS1000010160 (22:41435247 C>A,T), RS1000217440 (22:41439446 T>C,G), RS1000227267 (22:41445918 T>C), RS1000253145 (22:41442170 G>C), RS1000305982 (22:41444025 C>T), RS1000374010 (22:41448265 G>A), RS1000409721 (22:41447601 C>G,T), RS1000483282 (22:41447811 G>T), RS1000699237 (22:41438026 C>T), RS1000751105 (22:41446763 A>G), RS1001223324 (22:41435585 G>A,C), RS1001297081 (22:41435791 C>G), RS1001327416 (22:41447262 C>T), RS1001610096 (22:41448234 G>A,C), RS1001763397 (22:41442997 C>T)

Disease associations

OMIM: gene MIM:607396 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001509_6	Vitiligo	7.000000e-10
GCST004521_55	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST005038_59	Allergic disease (asthma, hay fever or eczema)	5.000000e-14
GCST005232_52	Neuroticism	3.000000e-18
GCST009720_75	Asthma	1.000000e-08
GCST010002_83	Refractive error	2.000000e-27
GCST010143_2	Meat-related diet	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	5
Dexamethasone	increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Irinotecan	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Coumestrol	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Progesterone	affects cotreatment, increases expression	1
Selenium	decreases expression, affects cotreatment	1
Gonadal Steroid Hormones	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1

Clinical trials (associated diseases)

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