THEMIS2

Summary

THEMIS2 (thymocyte selection associated family member 2, HGNC:16839) is a protein-coding gene on chromosome 1p35.3, encoding Protein THEMIS2 (Q5TEJ8). May constitute a control point in macrophage inflammatory response, promoting LPS-induced TLR4-mediated TNF production.

Predicted to be involved in T cell receptor signaling pathway and regulation of B cell activation. Predicted to be active in cytoplasm and nucleus.

Source: NCBI Gene 9473 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 97 total
• MANE Select transcript: NM_001105556

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16839
Approved symbol	THEMIS2
Name	thymocyte selection associated family member 2
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	ICB-1, Icb-1
Ensembl gene	ENSG00000130775
Ensembl biotype	protein_coding
OMIM	617856
Entrez	9473

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000328928, ENST00000373921, ENST00000373925, ENST00000373927, ENST00000427466, ENST00000442118, ENST00000456990, ENST00000466068, ENST00000467258, ENST00000482828, ENST00000492877, ENST00000892134, ENST00000936344, ENST00000936345, ENST00000953043, ENST00000953044

RefSeq mRNA: 5 — MANE Select: NM_001105556 NM_001039477, NM_001105556, NM_001286113, NM_001286115, NM_004848

CCDS: CCDS30653, CCDS30654, CCDS41290, CCDS65461

Canonical transcript exons

ENST00000373921 — 6 exons

Exon	Start	End
ENSE00001312249	27881971	27883043
ENSE00001461931	27872544	27872665
ENSE00003494363	27885295	27885451
ENSE00003552769	27876588	27876728
ENSE00003626599	27879644	27880054
ENSE00003850999	27885867	27886675

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.9018 / max 2534.8041, expressed in 1524 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1750	38.1892	1518
1752	0.2366	103
1755	0.1776	37
1759	0.1718	51
1760	0.0728	16
1758	0.0539	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.00	gold quality
mononuclear cell	CL:0000842	98.90	gold quality
leukocyte	CL:0000738	98.87	gold quality
granulocyte	CL:0000094	98.33	gold quality
blood	UBERON:0000178	97.90	gold quality
spleen	UBERON:0002106	97.49	gold quality
bone marrow cell	CL:0002092	96.10	gold quality
right lung	UBERON:0002167	95.66	gold quality
bone marrow	UBERON:0002371	94.20	gold quality
upper lobe of left lung	UBERON:0008952	93.23	gold quality
vermiform appendix	UBERON:0001154	92.73	gold quality
upper lobe of lung	UBERON:0008948	92.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.06	gold quality
gall bladder	UBERON:0002110	91.78	gold quality
lymph node	UBERON:0000029	91.61	gold quality
spinal cord	UBERON:0002240	89.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.39	gold quality
caecum	UBERON:0001153	88.01	gold quality
omental fat pad	UBERON:0010414	87.77	gold quality
peritoneum	UBERON:0002358	87.70	gold quality
right testis	UBERON:0004534	87.22	gold quality
lung	UBERON:0002048	87.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.89	gold quality
left testis	UBERON:0004533	86.74	gold quality
trabecular bone tissue	UBERON:0002483	85.73	gold quality
testis	UBERON:0000473	85.58	gold quality
small intestine	UBERON:0002108	85.50	gold quality
right coronary artery	UBERON:0001625	85.15	gold quality
descending thoracic aorta	UBERON:0002345	84.96	gold quality
rectum	UBERON:0001052	84.48	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	37.34
E-MTAB-9221	yes	26.29
E-MTAB-6678	yes	23.63
E-MTAB-6701	yes	20.57
E-MTAB-8142	yes	17.48
E-HCAD-1	yes	15.70
E-CURD-122	yes	12.64
E-MTAB-9801	yes	6.83
E-CURD-88	yes	5.96
E-MTAB-5061	no	3.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting THEMIS2, 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-5193	100.00	67.26	1744
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987

Literature-anchored findings (GeneRIF, showing 11)

• Increased icb-1 mRNA levels could be observed both in monocytic and granulocytic differentiation in maturing HL-60 cells. (PMID:12191572)
• The novel interferon-gamma inducible gene icb-1 is identified and its effects on the response of ovarian cancer cells to interferon-gamma are described (PMID:16219472)
• Data suggest that SNP rs1467465 of human gene icb-1 might affect breast cancer susceptibility. (PMID:19308812)
• Identification of ICB-1 as a new player in endocrine-related cancer. (PMID:19942713)
• Data show that a highly significant positive correlation of icb-1 transcript levels with c-erbB2 (HER2) expression (p <.0001). (PMID:20569072)
• These findings together with the observed co-expression of icb-1 with E-cadherin in breast cancer samples support an important role of the icb-1 gene in cancer cell differentiation. (PMID:21455565)
• Data of this study suggest that icb-1 might exert a tumor-suppressor function in breast cancer and that its loss might confer relative resistance of breast cancer cells to apoptotic drugs. (PMID:22565810)
• Themis2 and Themis1 exhibit the same potential to restore T cell development and T cell receptor-mediated signaling in Themis1-deficient mice. (PMID:22732588)
• Loss of icb-1 expression accelerated proliferation of SK-OV-3, OVCAR-3 and OAW-42 cells and led to upregulation of ovarian cancer biomarkers like KLK10 and CLDN16. (PMID:23474491)
• SNP rs1467465 of the human gene icb-1 might affect susceptibility to ovarian cancer. (PMID:24826199)
• Icb-1 expression inhibits growth and fulvestrant response of breast cancer cells and affects survival of breast cancer patients. (PMID:33389102)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	themis2	ENSDARG00000058964
mus_musculus	Themis2	ENSMUSG00000037731
rattus_norvegicus	Themis2	ENSRNOG00000012965

Paralogs (1): THEMIS (ENSG00000172673)

Protein

Protein identifiers

Protein THEMIS2 — Q5TEJ8 (reviewed: Q5TEJ8)

Alternative names: Induced by contact to basement membrane 1 protein, Thymocyte-expressed molecule involved in selection protein 2

All UniProt accessions (4): Q5TEJ8, H7C124, Q5TEK2, X6RK39

UniProt curated annotations — full annotation on UniProt →

Function. May constitute a control point in macrophage inflammatory response, promoting LPS-induced TLR4-mediated TNF production. Determines the threshold for activation of B cells by low-affinity and low-avidity ligands via PLCG2 activation and its downstream pathways.

Subunit / interactions. Interacts with VAV1. Interacts with LAT. Interacts constitutively with GRB2, LYN and PLCG2; these interactions increase the activation of PLCG2 and its downstream pathways following B cell receptor stimulation.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in different endometrial adenocarcinoma cell lines and various other cell lines apart from the prostate cell line LNCaP and the ovarian cancer cell line BG1.

Post-translational modifications. Phosphorylation at Tyr-632 is induced by LPS. Phosphorylated by Src kinases (Lck or Fyn) following BCR engagement.

Induction. By contact to a reconstituted basement membrane.

Similarity. Belongs to the themis family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q5TEJ8-1	1	yes
Q5TEJ8-2	2, ICB1-beta
Q5TEJ8-3	3, ICB1-gamma
Q5TEJ8-4	4
Q5TEJ8-5	5
Q5TEJ8-6	6

RefSeq proteins (5): NP_001034566, NP_001099026, NP_001273042, NP_001273044, NP_004839 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025946	CABIT_dom	Domain
IPR039671	THEMIS	Family

Pfam: PF12736

UniProt features (21 total): splice variant 7, sequence conflict 5, region of interest 3, sequence variant 2, modified residue 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TEJ8-F1	74.86	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): 593, 632

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 260 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, BROWNE_HCMV_INFECTION_12HR_UP, WIELAND_UP_BY_HBV_INFECTION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, GNF2_MCL1, GNF2_S100A4, MODULE_480

GO Biological Process (5): inflammatory response (GO:0006954), cell adhesion (GO:0007155), T cell receptor signaling pathway (GO:0050852), regulation of B cell activation (GO:0050864), immune system process (GO:0002376)

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

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	1
cellular process	1
antigen receptor-mediated signaling pathway	1
B cell activation	1
regulation of lymphocyte activation	1
biological_process	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THEMIS2	LYN	P07948	548
THEMIS2	GRB2	P29354	535
THEMIS2	SRGN	P10124	520
THEMIS2	GAREM2	Q75VX8	475
THEMIS2	GAREM1	Q9H706	465
THEMIS2	CNR2	P34972	450
THEMIS2	TMEM210	A6NLX4	447
THEMIS2	CD53	P19397	446
THEMIS2	TYROBP	O43914	436
THEMIS2	SASH3	O75995	426
THEMIS2	MNDA	P41218	422
THEMIS2	XKR8	Q9H6D3	421
THEMIS2	SMPDL3B	Q92485	416
THEMIS2	PCGF5	Q86SE9	406
THEMIS2	PIK3AP1	Q6ZUJ8	405

IntAct

14 interactions, top by confidence:

A	B	Type	Score
NOTCH2NLA	THEMIS2	psi-mi:“MI:0915”(physical association)	0.670
THEMIS2	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.670
HSPB2	THEMIS2	psi-mi:“MI:0915”(physical association)	0.370
EIF4E3	TBC1D4	psi-mi:“MI:0914”(association)	0.350
DDX55	U2SURP	psi-mi:“MI:2364”(proximity)	0.270
LIN28B	MEX3A	psi-mi:“MI:2364”(proximity)	0.270
SMNDC1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
THEMIS2	ddl	psi-mi:“MI:0915”(physical association)	0.000
glnF	THEMIS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): NOTCH2NL (Two-hybrid), THEMIS2 (Affinity Capture-MS), THEMIS2 (Two-hybrid), THEMIS2 (Affinity Capture-MS), THEMIS2 (Affinity Capture-MS), THEMIS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LI67, A0JM98, A1L1H3, A6NAF9, A9CPT4, B5MCY1, E1C3S7, E7FDW8, F1R237, M0R4F8, O08721, O43187, O60522, O70173, P0C5Y8, P61407, Q0P5I2, Q1L5Z9, Q1L981, Q2T9U5, Q3HNM7, Q4QQS0, Q4R3G4, Q4R9F7, Q58EK5, Q5BIW4, Q5M7P8, Q5R810, Q5TEJ8, Q5VZ19, Q68DX3, Q6NU04, Q6NYX6, Q6ZN44, Q6ZU64, Q80VA5, Q8CFA1, Q8IZJ1, Q8R2S1, Q8TF17

Diamond homologs: A5D789, A5PF62, Q5TEJ8, Q8BGW0, Q8N1K5, Q91YX0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1227 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27876725:CAGGG:C	donor_loss	1.0000
1:27876726:AGGGT:A	donor_loss	1.0000
1:27876727:GG:G	donor_gain	1.0000
1:27876728:GG:G	donor_gain	1.0000
1:27876729:G:GG	donor_gain	1.0000
1:27876730:T:G	donor_loss	1.0000
1:27880050:GCACA:G	donor_gain	1.0000
1:27880051:CACAG:C	donor_loss	1.0000
1:27880053:CA:C	donor_gain	1.0000
1:27880054:AGTG:A	donor_loss	1.0000
1:27880055:G:C	donor_loss	1.0000
1:27880055:G:GG	donor_gain	1.0000
1:27880056:T:A	donor_loss	1.0000
1:27880057:GAGTT:G	donor_loss	1.0000
1:27885293:A:G	acceptor_gain	1.0000
1:27885294:G:GG	acceptor_gain	1.0000
1:27872662:GAGG:G	donor_gain	0.9900
1:27872664:GG:G	donor_gain	0.9900
1:27872665:GG:G	donor_gain	0.9900
1:27873848:TGG:T	donor_gain	0.9900
1:27876582:CCGCA:C	acceptor_loss	0.9900
1:27876583:CGCA:C	acceptor_loss	0.9900
1:27876584:GCA:G	acceptor_loss	0.9900
1:27876585:CAGGC:C	acceptor_loss	0.9900
1:27876586:A:AG	acceptor_gain	0.9900
1:27876586:A:AT	acceptor_loss	0.9900
1:27876587:G:GG	acceptor_gain	0.9900
1:27880051:CACA:C	donor_gain	0.9900
1:27880052:ACA:A	donor_gain	0.9900
1:27880058:AGTTG:A	donor_loss	0.9900

AlphaMissense

4170 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27882316:T:C	F331S	0.984
1:27882265:T:C	F314S	0.981
1:27882264:T:C	F314L	0.980
1:27882266:C:A	F314L	0.980
1:27882266:C:G	F314L	0.980
1:27882613:T:C	F430S	0.980
1:27882315:T:C	F331L	0.978
1:27882317:C:A	F331L	0.978
1:27882317:C:G	F331L	0.978
1:27882445:T:C	L374P	0.978
1:27880042:G:C	A212P	0.974
1:27882507:T:C	C395R	0.974
1:27879907:T:C	F167L	0.972
1:27879909:C:A	F167L	0.972
1:27879909:C:G	F167L	0.972
1:27881992:T:C	I223T	0.972
1:27882051:T:C	F243L	0.970
1:27882053:T:A	F243L	0.970
1:27882053:T:G	F243L	0.970
1:27882298:G:C	R325P	0.970
1:27882370:T:A	V349E	0.969
1:27882334:T:C	L337P	0.968
1:27882688:T:A	V455D	0.968
1:27882334:T:A	L337H	0.966
1:27882316:T:G	F331C	0.965
1:27882612:T:C	F430L	0.965
1:27882614:C:A	F430L	0.965
1:27882614:C:G	F430L	0.965
1:27882620:G:C	E432D	0.965
1:27882620:G:T	E432D	0.965

dbSNP variants (sampled 300 via entrez): RS1000153809 (1:27885422 G>A), RS1000268771 (1:27885783 C>A,G), RS1000750738 (1:27877548 C>T), RS1000769707 (1:27875708 AT>A,ATT), RS1000814719 (1:27879416 G>A,C,T), RS1000979734 (1:27881083 AAAT>A), RS1001120885 (1:27877454 T>C), RS1001282705 (1:27881286 T>A), RS1001530523 (1:27871575 T>C), RS1001561677 (1:27871891 C>A,T), RS1001591332 (1:27872197 T>C), RS1001770490 (1:27876575 C>G,T), RS1001905379 (1:27870551 A>T), RS1002079914 (1:27870968 A>C,G), RS1002208728 (1:27882831 C>T)

Disease associations

OMIM: gene MIM:617856 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST008155_32	Waist-hip ratio	9.000000e-06
GCST90002388_601	Lymphocyte count	1.000000e-17
GCST90002393_120	Monocyte count	2.000000e-12
GCST90002400_21	Plateletcrit	8.000000e-17
GCST90002401_10	Platelet distribution width	2.000000e-10
GCST90002401_9	Platelet distribution width	5.000000e-11
GCST90002404_458	Red cell distribution width	3.000000e-11
GCST90002407_393	White blood cell count	3.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects reaction, increases expression, affects expression	4
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Silicon Dioxide	increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
OTX015	increases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
trichostatin A	affects expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
pentanal	increases expression	1
avobenzone	increases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Aldehydes	increases expression	1
Amphotericin B	decreases expression	1
Benzo(a)pyrene	affects methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1I2	Abcam A-549 THEMIS2 KO 2	Cancer cell line	Male
CVCL_B2QK	Abcam A-549 THEMIS2 KO 1	Cancer cell line	Male

Clinical trials (associated diseases)

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