SSX2

Summary

SSX2 (SSX family member 2, HGNC:11336) is a protein-coding gene on chromosome Xp11.22, encoding Protein SSX2 (Q16385). Could act as a modulator of transcription.

The product of this gene belongs to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors. They are also capable of eliciting spontaneous humoral and cellular immune responses in cancer patients, and are potentially useful targets in cancer vaccine-based immunotherapy. This gene, and also the SSX1 and SSX4 family members, have been involved in t(X;18)(p11.2;q11.2) translocations that are characteristically found in all synovial sarcomas. This translocation results in the fusion of the synovial sarcoma translocation gene on chromosome 18 to one of the SSX genes on chromosome X. The encoded hybrid proteins are likely responsible for transforming activity. Alternative splicing of this gene results in multiple transcript variants. This gene also has an identical duplicate, GeneID: 727837, located about 45 kb downstream in the opposite orientation on chromosome X.

Source: NCBI Gene 6757 — RefSeq curated summary.

At a glance

• MANE Select transcript: NM_175698

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11336
Approved symbol	SSX2
Name	SSX family member 2
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	HOM-MEL-40, HD21, MGC3884, MGC15364, MGC119055, CT5.2a
Ensembl gene	ENSG00000241476
Ensembl biotype	protein_coding
OMIM	300192
Entrez	6757

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000336777, ENST00000337502, ENST00000476392

RefSeq mRNA: 3 — MANE Select: NM_175698 NM_001278697, NM_003147, NM_175698

CCDS: CCDS14344, CCDS14345

Canonical transcript exons

ENST00000337502 — 8 exons

Exon	Start	End
ENSE00001294559	52696896	52697518
ENSE00001940648	52707112	52707178
ENSE00002023700	52704497	52704592
ENSE00002058646	52705128	52705242
ENSE00002082395	52705681	52705769
ENSE00002085802	52702581	52702630
ENSE00003521258	52697984	52698088
ENSE00003688556	52700443	52700578

Expression profiles

Bgee: expression breadth broad, 17 present calls, max score 75.53.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.52	gold quality
right testis	UBERON:0004534	59.78	gold quality
testis	UBERON:0000473	56.78	gold quality
left testis	UBERON:0004533	53.38	gold quality
right lobe of thyroid gland	UBERON:0001119	51.51	gold quality
thyroid gland	UBERON:0002046	45.66	gold quality
left lobe of thyroid gland	UBERON:0001120	44.33	gold quality
sural nerve	UBERON:0015488	43.04	gold quality
lower esophagus mucosa	UBERON:0035834	40.76	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
apex of heart	UBERON:0002098	34.44	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
cortex of kidney	UBERON:0001225	30.47	gold quality
placenta	UBERON:0001987	30.25	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
lymph node	UBERON:0000029	29.87	gold quality
liver	UBERON:0002107	29.62	gold quality
vermiform appendix	UBERON:0001154	29.13	gold quality
prefrontal cortex	UBERON:0000451	29.04	gold quality
duodenum	UBERON:0002114	28.14	gold quality
blood	UBERON:0000178	27.86	gold quality
tonsil	UBERON:0002372	27.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MMP2	Unknown

miRNA regulators (miRDB)

39 targeting SSX2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-6804-3P	98.72	64.82	852
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-3650	97.88	64.89	693

Literature-anchored findings (GeneRIF, showing 18)

• The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RABIN3, and a novel nuclear protein, SSX2IP. (PMID:12007189)
• existence of fusion with SYT in synovial sarcoma (PMID:12037676)
• We report the identification of an HLA-DR3-restricted epitope mapping to the 37-51 region of SSX-2. (PMID:15596411)
• RT-PCR detection of SSX2 in paraffin-embedded tissue allowed for molecular diagnosis of synovial sarcoma. (PMID:15735574)
• demonstrate differentially expressed genes for the 2 major gene fusion variants in SS, chromosome 18 synovial sarcoma (SS18)/SSX1 and SS18/SSX2, and thereby suggest that these result in different downstream effects (PMID:16152617)
• Two kinds of cancer-testis antigen, SSX-2 and SSX-5 showed high-specific and high-frequent expression in hepatocellular carcinoma tissues, but neither of them could be detected in adjacent non-HCC tissues. (PMID:16546222)
• the initial events that likely occur when SYT-SSX2 is first expressed, and its dominant function in subverting the nuclear program of the stem cell, leading to its aberrant differentiation, as a first step toward transformation (PMID:21996728)
• The regulation of estrogen receptor alpha signaling by target proteins of SSX2 may explain the metastatic potential of breast cancer cells. (PMID:22344619)
• These results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. (PMID:24130893)
• SS18-SSX-induced Wnt/beta-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression. (PMID:24166495)
• SSX2, SSX3, and SSX4 are expressed in the lung tissue of only 3.5% early-stage non-small cell lung cancer patients. (PMID:24645645)
• The tumor-specific pattern of expression of SSX2. (PMID:24681846)
• primary autoantibodies against intracellular MM-specific tumor antigens SSX-2 and NY-ESO-1 are rare but functional in multiple myeloma patients after allogeneic stem cell transplantation (PMID:25078248)
• results reveal two important phenotypes of ectopic SSX2 expression that may drive/support tumorigenesis: First, immediate induction of genomic instability, and second, long-term support of tumor cell growth. (PMID:25363656)
• Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. (PMID:26947017)
• We conclude from these findings that SSX2 expression in prostate cancer is not a driver of the epithelial to mesenchymal transition (EMT), but is involved in processes associated with EMT including loss of focal adhesion that may be related to tumor cell dissemination (PMID:27276714)
• co-expression of and interplay between Rab3IP and SSX2 during gastric cancer progression (PMID:30005870)
• A functional genetic screen identifies the Mediator complex as essential for SSX2-induced senescence. (PMID:31695025)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ssxb2	ENSMUSG00000023165
mus_musculus	Ssxb13	ENSMUSG00000035371
mus_musculus	Ssxa1	ENSMUSG00000062814
mus_musculus	Ssxb9	ENSMUSG00000068218
mus_musculus	Ssxb10	ENSMUSG00000068219
mus_musculus	Ssxb5	ENSMUSG00000071816
mus_musculus	Ssxb16	ENSMUSG00000079697
mus_musculus	Ssxb14	ENSMUSG00000079699
mus_musculus	Ssxb3	ENSMUSG00000079701
mus_musculus	Ssxb6	ENSMUSG00000079702
mus_musculus	Ssxb8	ENSMUSG00000079703
mus_musculus	Ssxb15	ENSMUSG00000079704
mus_musculus	Ssxb1	ENSMUSG00000079705
rattus_norvegicus	Ssx1	ENSRNOG00000027850
rattus_norvegicus	Ssx2	ENSRNOG00000049427

Paralogs (7): SSX1 (ENSG00000126752), SSX5 (ENSG00000165583), SSX3 (ENSG00000165584), SSX7 (ENSG00000187754), SSX4 (ENSG00000268009), SSX2B (ENSG00000268447), SSX4B (ENSG00000269791)

Protein

Protein identifiers

Protein SSX2 — Q16385 (reviewed: Q16385)

Alternative names: Cancer/testis antigen 5.2, Synovial sarcoma, X breakpoint 2, Tumor antigen HOM-MEL-40

All UniProt accessions (1): Q16385

UniProt curated annotations — full annotation on UniProt →

Function. Could act as a modulator of transcription.

Subunit / interactions. Interacts via its N-terminal region with RAB3IP and SSX2IP.

Subcellular location. Nucleus.

Tissue specificity. Expressed at high level in the testis. Expressed at low level in thyroid. Not detected in tonsil, colon, lung, spleen, prostate, kidney, striated and smooth muscles. Detected in rhabdomyosarcoma and fibrosarcoma cell lines. Not detected in mesenchymal and epithelial cell lines.

Disease relevance. A chromosomal aberration involving SSX2 may be a cause of synovial sarcoma. Translocation t(X;18)(p11.2;q11.2). The translocation is specifically found in more than 80% of synovial sarcoma. The fusion products SSXT-SSX1 or SSXT-SSX2 are probably responsible for transforming activity. Heterogeneity in the position of the breakpoint can occur (low frequency).

Similarity. Belongs to the SSX family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16385-1	1	yes
Q16385-2	2

RefSeq proteins (3): NP_001265626, NP_003138, NP_783629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001909	KRAB	Domain
IPR003655	aKRAB	Domain
IPR019041	SSXRD_motif	Conserved_site
IPR036051	KRAB_dom_sf	Homologous_superfamily

Pfam: PF01352, PF09514

UniProt features (14 total): region of interest 3, modified residue 2, compositionally biased region 2, site 2, chain 1, domain 1, splice variant 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8HQY	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16385-F1	69.63	0.28

Functional residue map

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

Catalytic / active sites (2): 68–69 (breakpoint for translocation to form the ssxt-ssx2 fusion protein (rare)); 110–111 (breakpoint for translocation to form the ssxt-ssx2 fusion protein)

Post-translational modifications (2): 123, 108

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 39 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, BROWNE_HCMV_INFECTION_8HR_UP, BROWNE_HCMV_INFECTION_48HR_DN, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, MATTIOLI_MULTIPLE_MYELOMA_SUBGROUPS, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, PARENT_MTOR_SIGNALING_UP, LIANG_SILENCED_BY_METHYLATION_2, MULLIGHAN_NPM1_MUTATED_SIGNATURE_1_UP, chrXp11, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A12, NAKAYAMA_SOFT_TISSUE_TUMORS_PCA2_UP, TAVAZOIE_METASTASIS, ZHONG_RESPONSE_TO_AZACITIDINE_AND_TSA_UP

GO Biological Process (1): regulation of DNA-templated transcription (GO:0006355)

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

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

51 interactions, top by confidence:

A	B	Type	Score
SSX2IP	SSX2	psi-mi:“MI:0915”(physical association)	0.720
SSX2	SSX2IP	psi-mi:“MI:0407”(direct interaction)	0.720
SSX2	SSX2IP	psi-mi:“MI:0915”(physical association)	0.720
SSX2	SSX2IP	psi-mi:“MI:0403”(colocalization)	0.720
SSX2	RAB3IP	psi-mi:“MI:0915”(physical association)	0.670
AKAP9	SSX2	psi-mi:“MI:0915”(physical association)	0.670
SSX2	AKAP9	psi-mi:“MI:0915”(physical association)	0.670
RAB3IP	SSX2	psi-mi:“MI:0915”(physical association)	0.670
SSX2	ZBED1	psi-mi:“MI:0915”(physical association)	0.560
SSX2	KRT40	psi-mi:“MI:0915”(physical association)	0.560
TAX1BP1	SSX2	psi-mi:“MI:0915”(physical association)	0.560
SSX2	SYCE1	psi-mi:“MI:0915”(physical association)	0.560
ZMIZ2	SSX2	psi-mi:“MI:0915”(physical association)	0.560
BLZF1	SSX2	psi-mi:“MI:0915”(physical association)	0.560
MAGEC2	SSX2	psi-mi:“MI:0915”(physical association)	0.560
KRT40	SSX2	psi-mi:“MI:0915”(physical association)	0.560
SYCE1	SSX2	psi-mi:“MI:0915”(physical association)	0.560
SSX2	ZMIZ2	psi-mi:“MI:0915”(physical association)	0.560
ZBED1	SSX2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (67): BLZF1 (Two-hybrid), TAX1BP1 (Two-hybrid), ZBED1 (Two-hybrid), AKAP9 (Two-hybrid), MAGEC2 (Two-hybrid), ZMIZ2 (Two-hybrid), SYCE1 (Two-hybrid), RAB3IP (Two-hybrid), SSX2IP (Two-hybrid), KRT40 (Two-hybrid), SSX2B (Affinity Capture-MS), SSX3 (Affinity Capture-MS), SSX7 (Affinity Capture-MS), SSX3 (Affinity Capture-MS), SSX5 (Affinity Capture-MS)

ESM2 similar proteins: A6H5X4, B1AUS7, D0QMC3, O35368, O60224, O60225, P0C6Y7, P0DOV1, P0DOV2, P23497, P41218, Q15361, Q16384, Q16385, Q16666, Q2KIN0, Q3U827, Q3ZCI6, Q4R7Q1, Q504N7, Q5H9L4, Q5I0E2, Q5I0J8, Q5RAK3, Q5RCZ8, Q5RD14, Q5W0A0, Q62187, Q6K0P9, Q71F23, Q7RTT3, Q7RTT4, Q7RTT5, Q7RTT6, Q86T96, Q8BV49, Q8BVM9, Q8C0V1, Q8C6C7, Q8CGE8

Diamond homologs: B1AUS7, O60224, O60225, P0C6Y7, Q16384, Q16385, Q7RTT3, Q7RTT4, Q7RTT5, Q7RTT6, Q8BFS8, Q96EQ9, Q99909, Q9NQV7, Q9NQW5, Q6ZMS7, A0A163UT06, A2AGX3, A6QPM3, E9Q3T6, O75626, P52736, Q13029, Q3UZD5, Q5R5M1, Q60636, Q63755, Q6P2A1, Q6PGE4, Q80V63, Q86UQ0, Q8BZ97, Q8TD17, Q9GZV8, Q9NQV5, Q9NQV8, Q9NQX0, Q9QZP2, Q9UDV7, Q9UKN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1139 predictions. Top by Δscore:

Variant	Effect	Δscore
X:52697982:A:AC	donor_gain	1.0000
X:52697983:C:CC	donor_gain	1.0000
X:52697983:CG:C	donor_gain	1.0000
X:52697983:CGG:C	donor_gain	1.0000
X:52698001:T:TA	donor_gain	1.0000
X:52700581:T:C	acceptor_gain	1.0000
X:52700581:T:TC	acceptor_gain	1.0000
X:52700583:A:C	acceptor_gain	1.0000
X:52700586:A:AC	acceptor_gain	1.0000
X:52700586:A:C	acceptor_gain	1.0000
X:52700588:G:GC	acceptor_gain	1.0000
X:52702628:CAA:C	acceptor_gain	1.0000
X:52702631:C:CC	acceptor_gain	1.0000
X:52704489:CTACT:C	donor_loss	1.0000
X:52704491:ACT:A	donor_loss	1.0000
X:52704492:CT:C	donor_loss	1.0000
X:52704493:TCACC:T	donor_loss	1.0000
X:52704494:CA:C	donor_loss	1.0000
X:52704495:A:AC	donor_gain	1.0000
X:52704495:A:C	donor_loss	1.0000
X:52704495:AC:A	donor_gain	1.0000
X:52704496:C:CC	donor_gain	1.0000
X:52704496:CC:C	donor_gain	1.0000
X:52704496:CCCTG:C	donor_gain	1.0000
X:52704593:C:CC	acceptor_gain	1.0000
X:52705131:G:C	donor_gain	1.0000
X:52705141:AG:A	donor_gain	1.0000
X:52705149:A:AC	donor_gain	1.0000
X:52705150:C:CC	donor_gain	1.0000
X:52705150:CTTT:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS112553841 (X:52698505 G>T), RS113462432 (X:52698659 G>C), RS113958409 (X:52699684 C>T), RS1156467888 (X:52701191 A>T), RS1158343869 (X:52698012 G>A,C,T), RS1160087127 (X:52698476 A>G), RS1163062342 (X:52697921 C>T), RS1163576014 (X:52698345 T>C), RS1167500038 (X:52697769 C>A), RS1169845465 (X:52698209 T>G), RS1170710199 (X:52697750 G>A), RS1172844522 (X:52698195 C>A), RS1174929312 (X:52698484 A>G), RS1178237506 (X:52697938 T>C), RS1180105490 (X:52698384 G>A)

Disease associations

OMIM: gene MIM:300192 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	affects expression, increases expression	4
sodium arsenite	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Cadmium	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Phenylmercuric Acetate	increases expression	1
Testosterone	decreases expression, affects cotreatment	1

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_7146	SYO-1	Cancer cell line	Female
CVCL_D880	Fuji	Cancer cell line	Female
CVCL_F682	A2243	Cancer cell line
CVCL_N585	STS255	Cancer cell line	Female
CVCL_N586	CME-1	Transformed cell line	Female
CVCL_N588	1273/99	Cancer cell line	Sex unspecified
CVCL_VE84	NCC-SS2-C1	Cancer cell line	Female
CVCL_WU91	SCS214	Cancer cell line
CVCL_ZV94	OSA 1777	Cancer cell line	Female

Clinical trials (associated diseases)

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