SSH3

Summary

SSH3 (slingshot protein phosphatase 3, HGNC:30581) is a protein-coding gene on chromosome 11q13.2, encoding Protein phosphatase Slingshot homolog 3 (Q8TE77). Protein phosphatase which may play a role in the regulation of actin filament dynamics.

The ADF (actin-depolymerizing factor)/cofilin family (see MIM 601442) is composed of stimulus-responsive mediators of actin dynamics. ADF/cofilin proteins are inactivated by kinases such as LIM domain kinase-1 (LIMK1; MIM 601329). The SSH family appears to play a role in actin dynamics by reactivating ADF/cofilin proteins in vivo (Niwa et al., 2002 [PubMed 11832213]).

Source: NCBI Gene 54961 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 145 total
• MANE Select transcript: NM_017857

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30581
Approved symbol	SSH3
Name	slingshot protein phosphatase 3
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20515, FLJ10928
Ensembl gene	ENSG00000172830
Ensembl biotype	protein_coding
OMIM	606780
Entrez	54961

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 22 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000308127, ENST00000308298, ENST00000376757, ENST00000525913, ENST00000527821, ENST00000529224, ENST00000531495, ENST00000532181, ENST00000532600, ENST00000532881, ENST00000534112, ENST00000882803, ENST00000882804, ENST00000882805, ENST00000882806, ENST00000882807, ENST00000882808, ENST00000882809, ENST00000882810, ENST00000882811, ENST00000882812, ENST00000929974, ENST00000929975, ENST00000929976, ENST00000959432, ENST00000959433, ENST00000959434, ENST00000959435

RefSeq mRNA: 1 — MANE Select: NM_017857 NM_017857

CCDS: CCDS8157

Canonical transcript exons

ENST00000308127 — 14 exons

Exon	Start	End
ENSE00001291046	67303530	67303691
ENSE00001330421	67304118	67304155
ENSE00002179929	67311591	67312592
ENSE00003465944	67310066	67310339
ENSE00003466951	67308412	67308458
ENSE00003504302	67309768	67309968
ENSE00003504945	67308174	67308302
ENSE00003597374	67306838	67306962
ENSE00003720793	67307371	67307436
ENSE00003735166	67307846	67307939
ENSE00003740119	67307549	67307737
ENSE00003746449	67307042	67307113
ENSE00003753297	67304773	67305007
ENSE00003789759	67309397	67309543

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0130 / max 327.2458, expressed in 1631 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115434	10.3902	1624
115433	0.8073	494
115435	0.5107	238
115436	0.3048	107

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.64	gold quality
pancreatic ductal cell	CL:0002079	96.26	gold quality
esophagus mucosa	UBERON:0002469	95.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.83	gold quality
cerebellar hemisphere	UBERON:0002245	94.57	gold quality
minor salivary gland	UBERON:0001830	94.52	gold quality
cerebellar cortex	UBERON:0002129	94.42	gold quality
right uterine tube	UBERON:0001302	94.23	gold quality
mucosa of transverse colon	UBERON:0004991	94.16	gold quality
vagina	UBERON:0000996	93.85	gold quality
metanephros cortex	UBERON:0010533	93.62	gold quality
saliva-secreting gland	UBERON:0001044	93.42	gold quality
skin of leg	UBERON:0001511	93.34	gold quality
esophagus	UBERON:0001043	93.26	gold quality
ectocervix	UBERON:0012249	93.24	gold quality
skin of abdomen	UBERON:0001416	93.21	gold quality
mucosa of stomach	UBERON:0001199	93.20	gold quality
mouth mucosa	UBERON:0003729	93.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.06	gold quality
transverse colon	UBERON:0001157	93.04	gold quality
endocervix	UBERON:0000458	92.91	gold quality
body of stomach	UBERON:0001161	92.89	gold quality
left ovary	UBERON:0002119	92.88	gold quality
cerebellum	UBERON:0002037	92.86	gold quality
right lobe of thyroid gland	UBERON:0001119	92.60	gold quality
right ovary	UBERON:0002118	92.57	gold quality
left lobe of thyroid gland	UBERON:0001120	92.37	gold quality
prostate gland	UBERON:0002367	91.97	gold quality
urinary bladder	UBERON:0001255	91.39	gold quality
thyroid gland	UBERON:0002046	91.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.06

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Expression of phosphatase-dead versions of SSH proteins, SSH1, SSH2 & SSH3 results in phosphorylation/inactivation of cofilin, changes in cytoskeleton organization, loss of cell polarity, and assembly of aberrant arrays of laminin-332 in keratinocytes. (PMID:17848544)
• SSH3 promotes malignant progression of HCC by activating FGF1-mediated FGF/FGFR pathway. (PMID:33275222)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-203d1.3	ENSDARG00000079591
mus_musculus	Ssh3	ENSMUSG00000034616
rattus_norvegicus	Ssh3	ENSRNOG00000018878

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), SSH1 (ENSG00000084112), DUSP3 (ENSG00000108861), PTPMT1 (ENSG00000110536), DUSP16 (ENSG00000111266), EPM2A (ENSG00000112425), DUSP22 (ENSG00000112679), DUSP1 (ENSG00000120129), DUSP4 (ENSG00000120875), STYXL1 (ENSG00000127952), DUSP9 (ENSG00000130829), DUSP26 (ENSG00000133878), DUSP5 (ENSG00000138166), DUSP6 (ENSG00000139318), SSH2 (ENSG00000141298), DUSP10 (ENSG00000143507), DUSP15 (ENSG00000149599), DUSP2 (ENSG00000158050), KASH5 (ENSG00000161609), DUSP19 (ENSG00000162999), DUSP7 (ENSG00000164086), DUSP18 (ENSG00000167065), DUSP8 (ENSG00000184545), DUSP28 (ENSG00000188542), DUSP29 (ENSG00000188716), DUSP21 (ENSG00000189037), STYX (ENSG00000198252), STYXL2 (ENSG00000198842), DUSP14 (ENSG00000276023), DUSP13A (ENSG00000293543)

Protein

Protein identifiers

Protein phosphatase Slingshot homolog 3 — Q8TE77 (reviewed: Q8TE77)

Alternative names: SSH-like protein 3

All UniProt accessions (5): Q8TE77, A0A087WWG1, C9JUG3, E9PIT5, E9PMS1

UniProt curated annotations — full annotation on UniProt →

Function. Protein phosphatase which may play a role in the regulation of actin filament dynamics. Can dephosphorylate and activate the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly.

Subunit / interactions. Does not bind to, or colocalize with, filamentous actin.

Subcellular location. Cytoplasm. Cytoskeleton. Nucleus.

Miscellaneous. Tyrosine phosphatase activity has not been demonstrated for this protein to date.

Similarity. Belongs to the protein-tyrosine phosphatase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8TE77-1	1, L	yes
Q8TE77-2	2
Q8TE77-3	3
Q8TE77-4	4
Q8TE77-5	5

RefSeq proteins (1): NP_060327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000340	Dual-sp_phosphatase_cat-dom	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR014876	DEK_C	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR043587	Phosphatase_SSH-like	Family
IPR043588	SSH-N	Domain

Pfam: PF00782, PF08766, PF23040

Catalyzed reactions (Rhea), 3 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)
• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (31 total): splice variant 7, modified residue 5, region of interest 5, compositionally biased region 4, sequence conflict 3, domain 2, sequence variant 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TE77-F1	62.79	0.21

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 (1): 413 (phosphocysteine intermediate)

Post-translational modifications (5): 2, 9, 37, 85, 87

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 133 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, HNF3ALPHA_Q6, JAEGER_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, AREB6_03, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, chr11q13, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, SRF_C, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ACTIN_FILAMENT_ORGANIZATION

GO Biological Process (4): actin cytoskeleton organization (GO:0030036), negative regulation of actin filament polymerization (GO:0030837), protein dephosphorylation (GO:0006470), dephosphorylation (GO:0016311)

GO Molecular Function (7): actin binding (GO:0003779), phosphoprotein phosphatase activity (GO:0004721), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	2
cytoskeleton organization	1
actin filament-based process	1
actin filament polymerization	1
regulation of actin filament polymerization	1
negative regulation of protein polymerization	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
dephosphorylation	1
protein modification process	1
phosphate-containing compound metabolic process	1
cytoskeletal protein binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
phosphoric ester hydrolase activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SSH3	LIMK1	P53667	891
SSH3	CFL1	P23528	890
SSH3	CFL2	Q9Y281	887
SSH3	PDXP	Q96GD0	555
SSH3	TESK1	Q15569	520
SSH3	LIMK2	P53671	507
SSH3	TESK2	Q96S53	451
SSH3	GPBP1	Q86WP2	447
SSH3	CEND1	Q8N111	426
SSH3	TLCD5	Q6ZRR5	424
SSH3	IGHMBP2	P38935	415
SSH3	AHI1	Q8N157	411
SSH3	RPGRIP1L	Q68CZ1	365
SSH3	ENKD1	Q9H0I2	325
SSH3	H8Y6P7	H8Y6P7	323

IntAct

17 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
NCK2	SSH3	psi-mi:“MI:0915”(physical association)	0.560
CAMK2D	ELP1	psi-mi:“MI:0914”(association)	0.530
TMEM248	TAF1	psi-mi:“MI:0914”(association)	0.350
SORT1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
SSH3	SLC4A1AP	psi-mi:“MI:0914”(association)	0.350
SSH3	HSPA8	psi-mi:“MI:0914”(association)	0.350
INF2	PIPSL	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
TRIM35	APAF1	psi-mi:“MI:0914”(association)	0.350
SSH3	CPT2	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
SSH3	PFAS	psi-mi:“MI:2364”(proximity)	0.270
NCK2	SSH3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (90): SSH3 (Affinity Capture-RNA), SSH3 (Affinity Capture-MS), SSH3 (Affinity Capture-MS), SSH3 (Affinity Capture-MS), SSH3 (Proximity Label-MS), SLC4A1AP (Affinity Capture-MS), ZNF330 (Affinity Capture-MS), HERC1 (Proximity Label-MS), RELA (Proximity Label-MS), CRYBG3 (Proximity Label-MS), NBR1 (Proximity Label-MS), CDK5RAP2 (Proximity Label-MS), PFAS (Proximity Label-MS), BIRC6 (Proximity Label-MS), KDM5C (Affinity Capture-MS)

ESM2 similar proteins: A1L168, A1L3T7, A6NGS2, A6QQF7, D4A8G3, O15049, P0C7N2, P0C7N4, P17257, P58660, Q08AY9, Q0V7M8, Q0VDN7, Q14BJ1, Q2NL23, Q3KP66, Q3LUD3, Q3UNU4, Q4LEZ3, Q566R4, Q571B6, Q5BJW5, Q5ND29, Q5RFZ7, Q5XIS1, Q6NSJ2, Q6P1G6, Q6Q0N2, Q7TN12, Q7TSI1, Q811W1, Q8BL43, Q8C7U1, Q8IV03, Q8K1S6, Q8K2P1, Q8N137, Q8N5H3, Q8TE77, Q8WWL2

Diamond homologs: A4IHU7, F1QWM2, O09112, O13632, O55737, O95147, P0C591, P0C592, P0C593, P0C594, P0C595, P0C596, P0C597, P0C598, P0C599, P0C5A0, P0C5A1, P0C5A2, P28562, P28563, P51452, Q05922, Q13115, Q13202, Q148W8, Q16828, Q16829, Q17QJ3, Q17QM8, Q1LWL2, Q29RA3, Q2KJ36, Q39491, Q4KL92, Q4RQD3, Q4V7N3, Q54T76, Q54Y32, Q556Y8, Q55BI8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SSH3	“up-regulates activity”	CFL1	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2727 predictions. Top by Δscore:

Variant	Effect	Δscore
11:67304155:GGTG:G	donor_loss	1.0000
11:67304156:G:GA	donor_loss	1.0000
11:67304157:T:A	donor_loss	1.0000
11:67306833:CCCA:C	acceptor_loss	1.0000
11:67306835:CAGGC:C	acceptor_loss	1.0000
11:67306836:A:AG	acceptor_gain	1.0000
11:67306836:A:T	acceptor_loss	1.0000
11:67306837:G:GT	acceptor_gain	1.0000
11:67306837:GGC:G	acceptor_gain	1.0000
11:67306837:GGCA:G	acceptor_gain	1.0000
11:67306922:GA:G	donor_gain	1.0000
11:67306973:G:GT	donor_gain	1.0000
11:67306980:A:T	donor_gain	1.0000
11:67307369:AG:A	acceptor_gain	1.0000
11:67307369:AGG:A	acceptor_gain	1.0000
11:67307370:GG:G	acceptor_gain	1.0000
11:67307370:GGG:G	acceptor_gain	1.0000
11:67307434:GTG:G	donor_gain	1.0000
11:67307547:A:AG	acceptor_gain	1.0000
11:67307547:AG:A	acceptor_gain	1.0000
11:67307548:G:GG	acceptor_gain	1.0000
11:67307548:GG:G	acceptor_gain	1.0000
11:67307548:GGGCC:G	acceptor_gain	1.0000
11:67307733:GGCGG:G	donor_gain	1.0000
11:67307734:GCGG:G	donor_gain	1.0000
11:67307734:GCGGG:G	donor_gain	1.0000
11:67307735:CGGG:C	donor_loss	1.0000
11:67307736:GGG:G	donor_loss	1.0000
11:67307738:G:A	donor_loss	1.0000
11:67307739:T:G	donor_loss	1.0000

AlphaMissense

4282 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:67307376:T:C	F181S	0.999
11:67307682:T:A	W246R	0.999
11:67307682:T:C	W246R	0.999
11:67307684:G:C	W246C	0.999
11:67307684:G:T	W246C	0.999
11:67307549:G:C	W201C	0.998
11:67307549:G:T	W201C	0.998
11:67307409:T:C	F192S	0.997
11:67307435:T:A	W201R	0.997
11:67307435:T:C	W201R	0.997
11:67306935:T:A	L146H	0.995
11:67307382:T:A	V183E	0.995
11:67309436:C:A	N367K	0.995
11:67309436:C:G	N367K	0.995
11:67309509:T:A	W392R	0.995
11:67309509:T:C	W392R	0.995
11:67309791:T:A	V411D	0.995
11:67309798:C:G	C413W	0.995
11:67306881:T:C	L128P	0.994
11:67307101:T:C	L175S	0.994
11:67307415:C:A	P194H	0.994
11:67307557:T:C	L204P	0.994
11:67307683:G:C	W246S	0.994
11:67309415:C:A	N360K	0.994
11:67309415:C:G	N360K	0.994
11:67309527:T:C	F398L	0.994
11:67309529:C:A	F398L	0.994
11:67309529:C:G	F398L	0.994
11:67309811:A:C	S418R	0.994
11:67309813:C:A	S418R	0.994

dbSNP variants (sampled 300 via entrez): RS1000378333 (11:67301660 T>C), RS1000876377 (11:67311381 G>C), RS1000892802 (11:67305895 C>T), RS1001366629 (11:67311234 C>A,T), RS1001398891 (11:67307714 G>C), RS1002043076 (11:67311988 G>A,T), RS1002249677 (11:67305902 T>C), RS1002400224 (11:67306534 G>A), RS1002835623 (11:67309298 A>C,G), RS1002888149 (11:67308953 C>T), RS1002891017 (11:67303456 C>T), RS1003223300 (11:67302025 C>G,T), RS1003833555 (11:67312528 C>A), RS1003930547 (11:67302346 G>A,C), RS1004104806 (11:67312233 A>T)

Disease associations

OMIM: gene MIM:606780 | 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
GCST007293_14	Body fat distribution (arm fat ratio)	9.000000e-08
GCST007294_129	Body fat distribution (trunk fat ratio)	8.000000e-28
GCST007294_95	Body fat distribution (trunk fat ratio)	1.000000e-35
GCST007295_43	Body fat distribution (leg fat ratio)	1.000000e-25
GCST007295_76	Body fat distribution (leg fat ratio)	1.000000e-21
GCST010242_449	HDL cholesterol levels	4.000000e-11
GCST010989_27	Body size at age 10	4.000000e-08
GCST90020029_345	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007789	BMI-adjusted waist circumference

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
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Valproic Acid	affects expression, increases methylation	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
lead acetate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
monomethylarsonous acid	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Dexamethasone	increases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Estradiol	affects expression	1

Clinical trials (associated diseases)

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