TUSC2

Summary

TUSC2 (tumor suppressor 2, mitochondrial calcium regulator, HGNC:17034) is a protein-coding gene on chromosome 3p21.31, encoding Tumor suppressor candidate 2 (O75896). May function as a tumor suppressor, inhibiting colony formation, causing G1 arrest and ultimately inducing apoptosis in homozygous 3p21.3 120-kb region-deficient cells.

Predicted to be involved in inflammatory response and regulation of mitochondrial membrane potential. Predicted to act upstream of or within several processes, including natural killer cell differentiation; neutrophil-mediated killing of gram-negative bacterium; and regulation of cytokine production. Predicted to be active in mitochondrion.

Source: NCBI Gene 11334 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_007275

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17034
Approved symbol	TUSC2
Name	tumor suppressor 2, mitochondrial calcium regulator
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	FUS1, PAP, C3orf11
Ensembl gene	ENSG00000114383
Ensembl biotype	protein_coding
OMIM	607052
Entrez	11334

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 nonsense_mediated_decay, 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000232496, ENST00000417867, ENST00000421918, ENST00000454201, ENST00000462137, ENST00000463304, ENST00000907123

RefSeq mRNA: 1 — MANE Select: NM_007275 NM_007275

CCDS: CCDS2819

Canonical transcript exons

ENST00000232496 — 3 exons

Exon	Start	End
ENSE00000768865	50324909	50326186
ENSE00001846567	50327954	50328223
ENSE00003544393	50326357	50326477

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 95.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.2188 / max 129.1825, expressed in 1813 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42319	22.6937	1813
42318	0.4940	238
42317	0.0311	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	95.26	gold quality
cingulate cortex	UBERON:0003027	94.94	gold quality
anterior cingulate cortex	UBERON:0009835	94.94	gold quality
right frontal lobe	UBERON:0002810	94.72	gold quality
type B pancreatic cell	CL:0000169	94.31	silver quality
Brodmann (1909) area 9	UBERON:0013540	94.27	gold quality
substantia nigra pars compacta	UBERON:0001965	94.26	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.01	gold quality
nucleus accumbens	UBERON:0001882	93.81	gold quality
amygdala	UBERON:0001876	93.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.62	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.46	gold quality
putamen	UBERON:0001874	93.40	gold quality
frontal cortex	UBERON:0001870	93.38	gold quality
caudate nucleus	UBERON:0001873	93.07	gold quality
neocortex	UBERON:0001950	93.06	gold quality
gastrocnemius	UBERON:0001388	92.99	gold quality
olfactory bulb	UBERON:0002264	92.99	silver quality
pons	UBERON:0000988	92.96	gold quality
triceps brachii	UBERON:0001509	92.81	gold quality
apex of heart	UBERON:0002098	92.51	gold quality
hypothalamus	UBERON:0001898	92.26	gold quality
muscle of leg	UBERON:0001383	92.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.21	gold quality
telencephalon	UBERON:0001893	92.08	gold quality
substantia nigra	UBERON:0002038	92.08	gold quality
gluteal muscle	UBERON:0002000	92.05	gold quality
right testis	UBERON:0004534	92.02	gold quality
cerebral cortex	UBERON:0000956	91.93	gold quality
midbrain	UBERON:0001891	91.88	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

88 targeting TUSC2, 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-188-3P	100.00	68.76	1240
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-512-3P	99.97	67.35	1049
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587

Literature-anchored findings (GeneRIF, showing 20)

• Overexpression of candidate tumor suppressor geneFUS1 isolated from the 3p21.3 homozygous deletionregion leads to G1 arrest and growth inhibition oflung cancer cells. (PMID:11593436)
• Myristoylation is required for Fus1-mediated tumor-suppressing activity and suggest a novel mechanism for the inactivation of tumor suppressors in lung cancer. (PMID:15126327)
• Data show that the recombinant FUS1 plasmid has been successfully cloned, which allows highly efficient FUS1 expression in E.coli strain Rosetta (DE3)2 plys. (PMID:17545076)
• These results suggest that miR-378 enhances cell survival, tumor growth, and angiogenesis through repression of the expression of two tumor suppressors, Sufu and Fus-1. (PMID:18077375)
• FUS1 gene and Fus1 protein abnormalities could be used to develop new strategies for molecular cancer therapy for a significant subset of lung tumors. (PMID:18172250)
• These results suggest that the three miRNAs are negative regulators of Fus1 expression in lung cancers. (PMID:19671678)
• The goal of this study was to analyze possible involvement of TUSC2 in malignant pleural mesothelioma. (PMID:19852844)
• Absence of tumor suppressor FUS1 protein expression is associated with bone and soft tissue sarcomas. (PMID:21273575)
• RNA sequence elements in FUS1 UTRs that regulate FUS1 protein express were identified. (PMID:21645495)
• The tumor suppressor gene TUSC2 (FUS1) sensitizes NSCLC to the AKT inhibitor MK2206 in LKB1-dependent manner. (PMID:24146957)
• TUSC2P and TUSC2 3’-UTR expression inhibits cell proliferation, survival, migration, invasion and colony formation, and increases tumor cell death. TUSC2P and TUSC2 3’-UTR bind to miRNAs and arrest their functions, leading to increased TUSC2 translation. (PMID:24394498)
• The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR. (PMID:26053020)
• FOXP1, TP53INP1, TNFAIP3, and TUSC2 were identified as miR-19a targets. (PMID:26367773)
• Data show that TUSC2 is a direct target of miR-584, which is transcriptionally regulated by TWIST1. (PMID:27661106)
• these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with Auranofin. (PMID:27845352)
• TUSC2P can suppresses the tumor function of esophageal squamous cell carcinoma by regulating TUSC2 expression and may also serve as a prognostic factor for esophageal squamous cell carcinoma patients. (PMID:30219035)
• Low TUSC2 expression is associated with bladder cancer. (PMID:30896880)
• MicroRNA-138 is a Prognostic Biomarker for Triple-Negative Breast Cancer and Promotes Tumorigenesis via TUSC2 repression. (PMID:31481748)
• The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein. (PMID:31973107)
• NEDD4 degrades TUSC2 to promote glioblastoma progression. (PMID:35167936)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tusc2b	ENSDARG00000025340
danio_rerio	tusc2a	ENSDARG00000099817
mus_musculus	Tusc2	ENSMUSG00000010054
rattus_norvegicus	Tusc2l1	ENSRNOG00000065209
caenorhabditis_elegans		WBGENE00007476

Protein

Protein identifiers

Tumor suppressor candidate 2 — O75896 (reviewed: O75896)

Alternative names: Fusion 1 protein, PDGFA-associated protein 2

All UniProt accessions (3): O75896, F2Z2A9, G3V0I0

UniProt curated annotations — full annotation on UniProt →

Function. May function as a tumor suppressor, inhibiting colony formation, causing G1 arrest and ultimately inducing apoptosis in homozygous 3p21.3 120-kb region-deficient cells.

Tissue specificity. Strong expression in heart, lung, skeletal muscle, kidney, and pancreas, followed by brain and liver, lowest levels in placenta.

Post-translational modifications. Myristoylation is required for tumor suppressor activity.

Similarity. Belongs to the TUSC2 family.

RefSeq proteins (1): NP_009206* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029393	FUS1	Family

Pfam: PF15000

UniProt features (4 total): initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75896-F1	78.76	0.46

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): 50, 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 199 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, GOBP_INFLAMMATORY_RESPONSE, TTTGTAG_MIR520D, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, CATTTCA_MIR203

GO Biological Process (10): natural killer cell differentiation (GO:0001779), phagocytosis (GO:0006909), inflammatory response (GO:0006954), negative regulation of interleukin-17 production (GO:0032700), positive regulation of interleukin-10 production (GO:0032733), cell maturation (GO:0048469), regulation of mitochondrial membrane potential (GO:0051881), neutrophil-mediated killing of gram-negative bacterium (GO:0070945), regulation of reactive oxygen species metabolic process (GO:2000377), defense response to Gram-negative bacterium (GO:0050829)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymphocyte differentiation	1
natural killer cell activation	1
endocytosis	1
defense response	1
negative regulation of cytokine production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
positive regulation of cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
cell development	1
cellular developmental process	1
anatomical structure maturation	1
regulation of membrane potential	1
defense response to Gram-negative bacterium	1
neutrophil-mediated killing of bacterium	1
regulation of metabolic process	1
reactive oxygen species metabolic process	1
defense response to bacterium	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

300 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUSC2	SUFU	Q9UMX1	822
TUSC2	EBLN2	Q6P2I7	588
TUSC2	KIF7	Q2M1P5	549
TUSC2	KIF27	Q86VH2	549
TUSC2	CASP3	P42574	538
TUSC2	APAF1	O14727	506
TUSC2	NPRL2	Q8WTW4	445
TUSC2	GLI2	P10070	428
TUSC2	GLI3	P10071	428
TUSC2	GLI1	P08151	411
TUSC2	BTRC	Q9Y297	385
TUSC2	XPO1	O14980	384
TUSC2	POLL	Q9UGP5	317
TUSC2	OR1M1	Q8NGA1	313
TUSC2	RASSF1	Q9NS23	311

IntAct

71 interactions, top by confidence:

A	B	Type	Score
TUSC2	MDFI	psi-mi:“MI:0915”(physical association)	0.780
MDFI	TUSC2	psi-mi:“MI:0915”(physical association)	0.780
RBPMS	TUSC2	psi-mi:“MI:0915”(physical association)	0.740
TUSC2	RBPMS	psi-mi:“MI:0915”(physical association)	0.740
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
TUSC2	FHL5	psi-mi:“MI:0915”(physical association)	0.560
FBXL19	MED19	psi-mi:“MI:0914”(association)	0.530
TAF8	TAF4	psi-mi:“MI:0914”(association)	0.530
TAF6L	SUPT3H	psi-mi:“MI:0914”(association)	0.530
RFFL	TUSC2	psi-mi:“MI:0914”(association)	0.530
TUSC2	HSPA8	psi-mi:“MI:0914”(association)	0.530
ABL	TUSC2	psi-mi:“MI:0414”(enzymatic reaction)	0.440
	TUSC2	psi-mi:“MI:0414”(enzymatic reaction)	0.440
PRODH	TUSC2	psi-mi:“MI:0915”(physical association)	0.400
MAPK9	TUSC2	psi-mi:“MI:0915”(physical association)	0.370
Hsph1	USP9Y	psi-mi:“MI:0914”(association)	0.350
TUSC2	NMT2	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
HSPA8	SBNO1	psi-mi:“MI:0914”(association)	0.350
FBXL16	POTEF	psi-mi:“MI:0914”(association)	0.350
CDK5	UNC119B	psi-mi:“MI:0914”(association)	0.350
SH2D3A	A2ML1	psi-mi:“MI:0914”(association)	0.350
F12		psi-mi:“MI:0914”(association)	0.350
TPGS1	PIK3R2	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): TUSC2 (Two-hybrid), TUSC2 (Two-hybrid), TUSC2 (Affinity Capture-MS), HSPA4L (Affinity Capture-MS), EBLN2 (Affinity Capture-MS), SGOL2 (Affinity Capture-MS), LRBA (Affinity Capture-MS), TUSC2 (Affinity Capture-MS), RBPMS (Two-hybrid), TUSC2 (Two-hybrid), TUSC2 (Two-hybrid), TUSC2 (Proximity Label-MS), TUSC2 (Proximity Label-MS), TUSC2 (Proximity Label-MS), TUSC2 (Affinity Capture-RNA)

ESM2 similar proteins: A2WXR5, A2Y0Q2, A2Y4R8, A9LMC0, B4GDK5, B8ADZ3, B8AMA8, B8B8I3, B8BJV8, E9PB15, F4I2J8, O54917, O60291, O75461, O75896, O81488, P0DOC8, P24051, P58268, P58269, Q08DY6, Q292G3, Q2R837, Q3T0B7, Q40359, Q5XEM9, Q60DW3, Q6IV56, Q6PI47, Q6XL73, Q6Z7F4, Q6ZWY3, Q717R8, Q71UM5, Q75IR6, Q7F2Z1, Q7LKZ5, Q84TV4, Q8H383, Q8LA16

Diamond homologs: O75896, Q93196, Q9WVF8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEDD4	“down-regulates quantity by destabilization”	TUSC2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

748 predictions. Top by Δscore:

Variant	Effect	Δscore
3:50320536:C:CC	acceptor_gain	1.0000
3:50322648:CTCA:C	donor_loss	1.0000
3:50322649:TCA:T	donor_loss	1.0000
3:50322650:CA:C	donor_loss	1.0000
3:50322651:ACCT:A	donor_loss	1.0000
3:50322652:C:G	donor_loss	1.0000
3:50326183:TGCC:T	acceptor_gain	1.0000
3:50326184:GCC:G	acceptor_gain	1.0000
3:50326185:CC:C	acceptor_gain	1.0000
3:50326185:CCC:C	acceptor_gain	1.0000
3:50326186:CC:C	acceptor_gain	1.0000
3:50326187:C:CC	acceptor_gain	1.0000
3:50326188:T:A	acceptor_loss	1.0000
3:50326190:CCA:C	acceptor_gain	1.0000
3:50326191:C:T	acceptor_gain	1.0000
3:50326191:CA:C	acceptor_gain	1.0000
3:50326192:A:C	acceptor_gain	1.0000
3:50326352:CTCAC:C	donor_loss	1.0000
3:50326353:TCA:T	donor_loss	1.0000
3:50326354:CA:C	donor_loss	1.0000
3:50326473:TAGAG:T	acceptor_gain	1.0000
3:50326474:AGAG:A	acceptor_gain	1.0000
3:50326475:GAG:G	acceptor_gain	1.0000
3:50326477:GC:G	acceptor_loss	1.0000
3:50326478:C:A	acceptor_loss	1.0000
3:50326478:C:CC	acceptor_gain	1.0000
3:50326479:T:A	acceptor_loss	1.0000
3:50326480:G:C	acceptor_gain	1.0000
3:50326480:G:GC	acceptor_gain	1.0000
3:50326482:G:C	acceptor_gain	1.0000

AlphaMissense

698 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:50326435:G:C	F63L	1.000
3:50326435:G:T	F63L	1.000
3:50326436:A:G	F63S	1.000
3:50326437:A:G	F63L	1.000
3:50326436:A:C	F63C	0.999
3:50326454:C:A	G57V	0.999
3:50326457:T:A	D56V	0.999
3:50326463:T:A	D54V	0.999
3:50326186:C:G	G90R	0.998
3:50326388:A:G	L79P	0.998
3:50326445:G:T	A60D	0.998
3:50326446:C:T	A60T	0.998
3:50326457:T:G	D56A	0.998
3:50326463:T:G	D54A	0.998
3:50326186:C:A	G90C	0.997
3:50326367:A:G	L86P	0.997
3:50326367:A:T	L86Q	0.997
3:50326434:A:C	Y64D	0.997
3:50326434:A:T	Y64N	0.997
3:50326437:A:C	F63V	0.997
3:50326440:C:T	E62K	0.997
3:50326445:G:A	A60V	0.997
3:50326448:A:G	L59P	0.997
3:50326451:T:C	D58G	0.997
3:50326455:C:A	G57W	0.997
3:50326458:C:G	D56H	0.997
3:50326463:T:C	D54G	0.997
3:50326464:C:G	D54H	0.997
3:50326468:G:C	F52L	0.997
3:50326468:G:T	F52L	0.997

dbSNP variants (sampled 300 via entrez): RS1000838885 (3:50326719 G>A), RS1000902242 (3:50327018 G>A,C), RS1001575032 (3:50329882 T>C), RS1001944988 (3:50328380 T>G), RS1002004757 (3:50330192 T>A), RS1005133549 (3:50326678 C>T), RS1005759500 (3:50329495 C>T), RS1005789269 (3:50329760 A>G), RS1006139346 (3:50328117 A>G), RS1008151258 (3:50327459 T>C), RS1009151385 (3:50328795 A>C,G), RS1009790843 (3:50328390 C>A,G,T), RS1013356687 (3:50328151 A>C,G,T), RS1013733558 (3:50327832 T>A), RS1014757622 (3:50327825 A>G)

Disease associations

OMIM: gene MIM:607052 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Leflunomide	decreases expression	2
Cisplatin	increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
arsenite	affects binding, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Ethyl Methanesulfonate	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Malathion	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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