SSH1

Summary

SSH1 (slingshot protein phosphatase 1, HGNC:30579) is a protein-coding gene on chromosome 12q24.11, encoding Protein phosphatase Slingshot homolog 1 (Q8WYL5). Protein phosphatase which regulates actin filament dynamics.

The protein encoded by this gene belongs to the slingshot homolog (SSH) family of phosphatases, which regulate actin filament dynamics. The SSH proteins dephosphorylate and activate the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Cofilin is inactivated by kinases such as LIM domain kinase-1 (LIMK1), which may also be dephosphorylated and inactivated by SSH proteins. The SSH family thus appears to play a role in actin dynamics by reactivating cofilin proteins. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 54434 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 193 total
• MANE Select transcript: NM_018984

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30579
Approved symbol	SSH1
Name	slingshot protein phosphatase 1
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1298, SSH1L
Ensembl gene	ENSG00000084112
Ensembl biotype	protein_coding
OMIM	606778
Entrez	54434

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000326470, ENST00000326495, ENST00000546433, ENST00000546697, ENST00000546812, ENST00000547381, ENST00000547862, ENST00000548522, ENST00000551165, ENST00000877978

RefSeq mRNA: 3 — MANE Select: NM_018984 NM_001161330, NM_001161331, NM_018984

CCDS: CCDS53825, CCDS55882, CCDS9121

Canonical transcript exons

ENST00000326495 — 15 exons

Exon	Start	End
ENSE00002348402	108778191	108789244
ENSE00002398142	108802322	108802368
ENSE00003485270	108800780	108800926
ENSE00003492984	108818249	108818313
ENSE00003527281	108792286	108792829
ENSE00003533305	108809693	108809758
ENSE00003552094	108807633	108807827
ENSE00003557506	108817038	108817159
ENSE00003587114	108805056	108805184
ENSE00003642216	108806301	108806394
ENSE00003647805	108811260	108811328
ENSE00003663469	108852638	108852678
ENSE00003680052	108799000	108799200
ENSE00003691806	108823258	108823361
ENSE00003842377	108857428	108857583

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 94.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.3627 / max 36.1110, expressed in 1662 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133172	2.5545	1236
133173	2.3156	1367
133171	0.4083	225
133166	0.0518	17
133165	0.0325	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	94.76	gold quality
stromal cell of endometrium	CL:0002255	91.47	gold quality
saphenous vein	UBERON:0007318	91.19	gold quality
secondary oocyte	CL:0000655	91.03	gold quality
trigeminal ganglion	UBERON:0001675	90.10	gold quality
lower lobe of lung	UBERON:0008949	89.59	gold quality
oocyte	CL:0000023	88.73	gold quality
mammary duct	UBERON:0001765	88.42	gold quality
endometrium epithelium	UBERON:0004811	87.73	silver quality
cauda epididymis	UBERON:0004360	87.59	gold quality
dorsal root ganglion	UBERON:0000044	87.38	gold quality
caput epididymis	UBERON:0004358	86.94	gold quality
tibialis anterior	UBERON:0001385	86.78	gold quality
epithelium of mammary gland	UBERON:0003244	86.60	gold quality
calcaneal tendon	UBERON:0003701	86.35	gold quality
corpus epididymis	UBERON:0004359	86.24	gold quality
superficial temporal artery	UBERON:0001614	86.22	gold quality
paraflocculus	UBERON:0005351	86.09	gold quality
muscle of leg	UBERON:0001383	85.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.78	gold quality
gastrocnemius	UBERON:0001388	85.57	gold quality
pericardium	UBERON:0002407	85.47	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.38	silver quality
islet of Langerhans	UBERON:0000006	85.33	gold quality
colonic epithelium	UBERON:0000397	85.05	gold quality
superior surface of tongue	UBERON:0007371	85.04	gold quality
cartilage tissue	UBERON:0002418	84.66	gold quality
cerebellar vermis	UBERON:0004720	84.58	silver quality
superior vestibular nucleus	UBERON:0007227	84.39	gold quality
vena cava	UBERON:0004087	84.25	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN

miRNA regulators (miRDB)

230 targeting SSH1, 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-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
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-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
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

Literature-anchored findings (GeneRIF, showing 32)

• SSH1 plays a critical role in cytokinesis by dephosphorylating and reactivating cofilin in later stages of mitosis (PMID:12807904)
• findings suggest that SSH1L is activated downstream of PI3K and plays a critical role in insulin-induced membrane protrusion by dephosphorylating and activating cofilin (PMID:14645219)
• SSH1L is locally activated by translocation to and association with F-actin in lamellipodia in response to neuregulin-1beta and 14-3-3 proteins negatively regulate SSH1L activity by sequestering it in the cytoplasm. (PMID:15159416)
• SSH1 mutations seen in patients with disseminated superficial actinic porokeratosis (PMID:15459975)
• a multi-protein complex consisting of SSH-1L, LIMK1, actin, and the scaffolding protein, 14-3-3zeta, is involved, along with the kinase, PAK4, in the regulation of ADF/cofilin activity (PMID:15660133)
• Ca2+-induced cofilin dephosphorylation is mediated by calcineurin-dependent activation of SSH1L (PMID:15671020)
• identified sites that play unique roles in the control of subcellular localization and F-actin-mediated activation of SSH1L (PMID:16513117)
• 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)
• PDGF participates in actin dynamics by dual regulation of cofilin activity via LIMK and SSH1L in aortic smooth muscle cells (PMID:18096821)
• the conserved SSH-N domain of slingshot-1 plays critical roles in P-cofilin recognition, F-actin-mediated activation, and subcellular localization of SSH1 (PMID:18809681)
• Results suggest that the formation of ROS by NADPH oxidases engages a SSH-1L-cofilin pathway to regulate cytoskeletal organization and cell migration. (PMID:19339277)
• These results implicate 14-3-3zeta/tau heterodimers as key regulators of SSH1 activity in keratinocytes and suggest they play a role in cytoskeleton remodeling during cell migration. (PMID:19371722)
• Data identify PKD as a central regulator of the cofilin signaling network via direct phosphorylation and regulation of SSH1L. (PMID:19567672)
• Results show the significance of SSH1L in estrogen-induced osteoblastogenic differentiation in favor of adipogenic differentiation from hMSCs. (PMID:21289500)
• identified Ser 402 as a new phosphorylation site within the catalytic domain of human slingshot 1 (SSH1). (PMID:21525957)
• A high expression of SSH-1L in peripheral eosinophils in acute exacerbations of asthma may play a role in the activation and migration of eosinophils. (PMID:21690039)
• EphA signaling promotes actin-based dendritic spine remodeling through slingshot 1. (PMID:22282498)
• Our work provides evidence that supports the positive role of SSH1L in the mechanism of stem cell differentiation into cardiomyocyte-like cells. (PMID:23247370)
• Results identify a novel frameshift mutation in this gene implicated in disseminated superficial actinic porokeratosis in 4 Chinese families (PMID:23834120)
• Thus this study provides evidence for a novel role of LIMK1 and SSH-1L in selectively regulating endothelial cell inflammation associated with intravascular coagulation. (PMID:24039253)
• Slingshot 1 downregulation in neuronal cells inactivates cofilin to facilitate HSV-1 replication. (PMID:24418541)
• Authors show that viral penetration-induced calcium release facilitated herpes simplex virus type 1 intracellular trafficking through activating slingshot 1 (SSH), a phosphatase regulating actin filament dynamics. (PMID:24670325)
• The association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions. (PMID:25100728)
• SSH1 binds to gelsolin via actin filaments in the cytosolic fraction. Gelsolin promoted solubilization of actin filaments and SSH1 in cell-free assays and in cultured cells. (PMID:25451266)
• Results reveal that SSH1L is upregulated in a subset of PCs and that the SSH1L/cofilin-1 signal pathway is associated positively in PC with cell migration. (PMID:25684665)
• the N-terminal PH-like domain plays a critical role in F-actin binding and F-actin-mediated activation of the cofilin-phosphatase activity of SSH1 (PMID:27865840)
• genetic variants at the genes SSH1 and ST8SIA1 were related to the genetic predisposition to early-onset periodontitis that is in part triggered by smoking (PMID:31537151)
• Role of SSH1 in colorectal cancer prognosis and tumor progression. (PMID:32020663)
• Slingshot homolog-1 amplifies mitochondrial abnormalities by distinctly impairing health and clearance of mitochondria. (PMID:36637427)
• SSH1 promotes progression of intrahepatic cholangiocarcinoma via p38 MAPK-CXCL8 axis. (PMID:36857607)
• Slingshot homolog-1-mediated Nrf2 sequestration tips the balance from neuroprotection to neurodegeneration in Alzheimer’s disease. (PMID:37463212)
• Dysregulated expression of slingshot protein phosphatase 1 (SSH1) disrupts circadian rhythm and WNT signaling associated to hepatocellular carcinoma pathogenesis. (PMID:37837551)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ssh1b	ENSDARG00000010031
danio_rerio	ssh1a	ENSDARG00000056780
mus_musculus	Ssh1	ENSMUSG00000042121
rattus_norvegicus	Ssh1	ENSRNOG00000000695

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), 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), SSH3 (ENSG00000172830), DUSP8 (ENSG00000184545), DUSP28 (ENSG00000188542), DUSP29 (ENSG00000188716), DUSP21 (ENSG00000189037), STYX (ENSG00000198252), STYXL2 (ENSG00000198842), DUSP14 (ENSG00000276023), DUSP13A (ENSG00000293543)

Protein

Protein identifiers

Protein phosphatase Slingshot homolog 1 — Q8WYL5 (reviewed: Q8WYL5)

Alternative names: SSH-like protein 1

All UniProt accessions (4): Q8WYL5, F8VS18, F8W1D9, H0YHR3

UniProt curated annotations — full annotation on UniProt →

Function. Protein phosphatase which regulates actin filament dynamics. Dephosphorylates and activates the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Inhibitory phosphorylation of cofilin is mediated by LIMK1, which may also be dephosphorylated and inactivated by this protein.

Subunit / interactions. Interacts with actin and this stimulates phosphatase activity. Also interacts with LIMK1 and with the 14-3-3 proteins YWHAB, YWHAG, YWHAQ, and YWHAZ. Interaction with 14-3-3 proteins inhibits phosphatase activity and also blocks recruitment to lamellipodia and stimulation by actin.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Lamellipodium. Cleavage furrow. Midbody.

Post-translational modifications. Phosphorylated. Inhibitory phosphorylation by PAK4 promotes binding to YWHAZ. Phosphorylation at Ser-978 is decreased by stimuli which promote actin reorganization and lamellipodia formation. Can be dephosphorylated and activated by PPP3CA/calcineurin A. Phosphorylation decreases immediately prior to telophase.

Miscellaneous. Tyrosine phosphatase activity has not been demonstrated for this protein to date. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Due to intron retention.

Similarity. Belongs to the protein-tyrosine phosphatase family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8WYL5-1	1, L	yes
Q8WYL5-2	2, S
Q8WYL5-3	3, B
Q8WYL5-4	4
Q8WYL5-5	5

RefSeq proteins (3): NP_001154802, NP_001154803, NP_061857* (*=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
IPR027233	DSP_SSH1	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 (43 total): splice variant 9, region of interest 8, compositionally biased region 8, modified residue 7, mutagenesis site 4, domain 2, sequence conflict 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYL5-F1	55.41	0.19

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): 393 (phosphocysteine intermediate)

Post-translational modifications (7): 2, 37, 57, 515, 576, 897, 978

Mutagenesis-validated functional residues (4):

Position	Phenotype
393	abrogates phosphatase activity.
458	impairs stimulation of phosphatase activity by actin but does not affect basal activity.
937	reduces binding to ywhab, ywhag, ywhaq and ywhaz. abolishes binding to ywhab, ywhag, ywhaq and ywhaz and increases assoc
978	reduces binding to ywhab, ywhag, ywhaq and ywhaz. abolishes binding to ywhab, ywhag, ywhaq and ywhaz and increases assoc

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 271 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GENTILE_RESPONSE_CLUSTER_D3, MOTAMED_RESPONSE_TO_ANDROGEN_UP, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_CELLULAR_RESPONSE_TO_ATP, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (12): cell morphogenesis (GO:0000902), protein dephosphorylation (GO:0006470), actin cytoskeleton organization (GO:0030036), negative regulation of actin filament polymerization (GO:0030837), positive regulation of synaptic plasticity (GO:0031915), regulation of protein metabolic process (GO:0051246), cellular response to ATP (GO:0071318), excitatory chemical synaptic transmission (GO:0098976), positive regulation of AMPA glutamate receptor clustering (GO:1904719), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), positive regulation of excitatory postsynaptic potential (GO:2000463), 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 (11): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), lamellipodium (GO:0030027), growth cone (GO:0030426), midbody (GO:0030496), cleavage furrow (GO:0032154), synapse (GO:0045202), membrane (GO:0016020), cell leading edge (GO:0031252), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
excitatory postsynaptic potential	2
phosphoprotein phosphatase activity	2
anatomical structure morphogenesis	1
dephosphorylation	1
protein modification process	1
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
regulation of synaptic plasticity	1
protein metabolic process	1
regulation of macromolecule metabolic process	1
regulation of primary metabolic process	1
response to ATP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
chemical synaptic transmission	1
AMPA glutamate receptor clustering	1
positive regulation of postsynaptic membrane organization	1
positive regulation of receptor clustering	1
regulation of AMPA glutamate receptor clustering	1
positive regulation of smooth muscle cell migration	1
vascular associated smooth muscle cell migration	1
regulation of vascular associated smooth muscle cell migration	1
positive regulation of signal transduction	1
modulation of excitatory postsynaptic potential	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 anatomical structure	1
intracellular membraneless organelle	1
membrane	1

Protein interactions and networks

STRING

1410 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SSH1	CFL1	P23528	949
SSH1	CFL2	Q9Y281	948
SSH1	LIMK1	P53667	937
SSH1	PRKD1	Q15139	724
SSH1	PDXP	Q96GD0	679
SSH1	HCLS1	P14317	632
SSH1	CTTN	Q14247	623
SSH1	YWHAZ	P29213	590
SSH1	LIMK2	P53671	574
SSH1	YWHAB	P31946	555
SSH1	PRKD3	O94806	546
SSH1	PAK4	O96013	546
SSH1	VCL	P18206	530
SSH1	PXN	P49023	528
SSH1	TESK1	Q15569	516

IntAct

39 interactions, top by confidence:

A	B	Type	Score
SEC23B	SEC24D	psi-mi:“MI:0914”(association)	0.920
SSH1	YWHAQ	psi-mi:“MI:0914”(association)	0.690
SSH1	YWHAQ	psi-mi:“MI:0407”(direct interaction)	0.690
SSH1	LIMK1	psi-mi:“MI:0403”(colocalization)	0.680
SSH1	LIMK1	psi-mi:“MI:0915”(physical association)	0.680
SSH1	LIMK1	psi-mi:“MI:0407”(direct interaction)	0.680
LIMK1	SSH1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.680
SSH1	CORO1B	psi-mi:“MI:0203”(dephosphorylation reaction)	0.580
SSH1	YWHAE	psi-mi:“MI:0914”(association)	0.530
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
SSH1	GSN	psi-mi:“MI:0914”(association)	0.530
SSH1	YWHAB	psi-mi:“MI:0914”(association)	0.530
SSH1	YWHAZ	psi-mi:“MI:0914”(association)	0.530
YWHAB	SSH1	psi-mi:“MI:0914”(association)	0.530
CORO1B	ARPC2	psi-mi:“MI:0914”(association)	0.500
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SSH1	Coro1b	psi-mi:“MI:0914”(association)	0.460
SSH1	NECTIN2	psi-mi:“MI:0915”(physical association)	0.400
SSH1	CFL1	psi-mi:“MI:0915”(physical association)	0.400
MYO1C	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SSH1	ARPC2	psi-mi:“MI:0914”(association)	0.350
Coro1b	Arpc2	psi-mi:“MI:0914”(association)	0.350
Arpc2	Coro1b	psi-mi:“MI:0914”(association)	0.350
SSH1	GSN	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): SSH1 (Affinity Capture-MS), SSH1 (Affinity Capture-MS), SSH1 (Affinity Capture-Western), SSH1 (Affinity Capture-Western), SSH1 (Affinity Capture-Western), SSH1 (Affinity Capture-Western), MYO5A (Affinity Capture-MS), SCIN (Affinity Capture-MS), YWHAE (Affinity Capture-MS), MYO5B (Proximity Label-MS), SVIL (Proximity Label-MS), MYH10 (Proximity Label-MS), ACTN4 (Proximity Label-MS), MYO1D (Proximity Label-MS), KIAA1671 (Proximity Label-MS)

ESM2 similar proteins: A1L170, A4IFJ0, A5D7K1, A6H7B4, A6NGG8, A6X8Z5, B1AXH1, D3ZMK9, O08696, O14513, O43151, P01099, P10637, P19103, P19332, Q08DN6, Q13522, Q2M1Z3, Q2TBN9, Q571I4, Q58CU6, Q5HYW2, Q5JSZ5, Q5M831, Q5M865, Q60664, Q640N3, Q68DA7, Q6DJE5, Q6PAC4, Q6ZW13, Q7LBC6, Q80U35, Q80U49, Q86YV5, Q8BG87, Q8C3W1, Q8C5R2, Q8C5W0, Q8WYL5

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

13 interactions.

A	Effect	B	Mechanism
SSH1	up-regulates	CORO1B	dephosphorylation
PRKD1	down-regulates	SSH1	phosphorylation
PRKD2	down-regulates	SSH1	phosphorylation
SSH1	“up-regulates activity”	CFL1	dephosphorylation
SSH1	“up-regulates activity”	CORO1B	dephosphorylation
SSH1	“down-regulates activity”	LIMK1	dephosphorylation
IRS4	“up-regulates activity”	SSH1	binding
PRKD1	“down-regulates activity”	SSH1	phosphorylation
PRKD2	“down-regulates activity”	SSH1	phosphorylation
PRKD3	“down-regulates activity”	SSH1	phosphorylation
PRKD1	“up-regulates activity”	SSH1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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
Activation of BAD and translocation to mitochondria	5	165.5×	7e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	146.0×	7e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	146.0×	7e-09
Activation of BH3-only proteins	5	107.9×	3e-08
RHO GTPases activate PKNs	5	69.0×	2e-07
Intrinsic Pathway for Apoptosis	5	63.7×	3e-07
EPHB-mediated forward signaling	5	57.7×	5e-07
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	47.0×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	70.5×	3e-06
intracellular protein localization	5	20.1×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	153
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3276 predictions. Top by Δscore:

Variant	Effect	Δscore
12:108792830:C:CC	acceptor_gain	1.0000
12:108800778:A:AC	donor_gain	1.0000
12:108800779:C:CT	donor_gain	1.0000
12:108800779:CTT:C	donor_gain	1.0000
12:108800779:CTTCG:C	donor_gain	1.0000
12:108800922:CAACC:C	acceptor_gain	1.0000
12:108800925:CC:C	acceptor_gain	1.0000
12:108800926:CC:C	acceptor_gain	1.0000
12:108800926:CCT:C	acceptor_loss	1.0000
12:108800927:C:CC	acceptor_gain	1.0000
12:108800928:T:C	acceptor_loss	1.0000
12:108805054:A:AC	donor_gain	1.0000
12:108805055:C:CC	donor_gain	1.0000
12:108805055:CGAG:C	donor_gain	1.0000
12:108805180:CGAAT:C	acceptor_gain	1.0000
12:108806296:CTTA:C	donor_loss	1.0000
12:108806297:TTAC:T	donor_loss	1.0000
12:108806298:TACCT:T	donor_loss	1.0000
12:108806299:A:C	donor_loss	1.0000
12:108806300:C:CG	donor_loss	1.0000
12:108806300:CCT:C	donor_gain	1.0000
12:108806392:GGCC:G	acceptor_loss	1.0000
12:108806395:C:CC	acceptor_gain	1.0000
12:108806395:C:CG	acceptor_loss	1.0000
12:108806396:T:C	acceptor_loss	1.0000
12:108807627:A:AC	donor_gain	1.0000
12:108807628:C:CC	donor_gain	1.0000
12:108807628:CTTA:C	donor_gain	1.0000
12:108807630:TA:T	donor_loss	1.0000
12:108807631:A:AC	donor_gain	1.0000

AlphaMissense

6928 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:108799012:A:G	I446T	1.000
12:108799022:A:G	Y443H	1.000
12:108799030:A:G	L440P	1.000
12:108799030:A:T	L440Q	1.000
12:108799041:A:C	F436L	1.000
12:108799041:A:T	F436L	1.000
12:108799042:A:C	F436C	1.000
12:108799042:A:G	F436S	1.000
12:108799043:A:G	F436L	1.000
12:108799054:G:T	P432H	1.000
12:108799130:A:C	Y407D	1.000
12:108799132:G:T	A406D	1.000
12:108799138:A:T	V404D	1.000
12:108799147:G:T	A401D	1.000
12:108799155:A:C	S398R	1.000
12:108799155:A:T	S398R	1.000
12:108799157:T:G	S398R	1.000
12:108799163:C:G	G396R	1.000
12:108799180:A:G	L390P	1.000
12:108799182:G:C	C389W	1.000
12:108800794:A:C	F378L	1.000
12:108800794:A:T	F378L	1.000
12:108800795:A:G	F378S	1.000
12:108800796:A:G	F378L	1.000
12:108800814:A:G	W372R	1.000
12:108800814:A:T	W372R	1.000
12:108802334:A:G	L330P	1.000
12:108802359:A:G	W322R	1.000
12:108802359:A:T	W322R	1.000
12:108809694:A:G	W179R	1.000

dbSNP variants (sampled 300 via entrez): RS1000031909 (12:108814119 G>A,C), RS1000047329 (12:108811840 T>C), RS1000077143 (12:108853453 G>A), RS1000107067 (12:108813611 G>C), RS1000199344 (12:108805850 G>A), RS1000313071 (12:108835696 G>C), RS1000326148 (12:108835327 G>C), RS1000332612 (12:108796221 T>G), RS1000334925 (12:108808783 T>C), RS1000374055 (12:108835365 T>TG), RS1000380622 (12:108841406 T>C), RS1000481037 (12:108846452 G>A), RS1000515762 (12:108794350 T>A), RS1000593626 (12:108829634 A>G), RS1000659427 (12:108803060 T>A)

Disease associations

OMIM: gene MIM:606778 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): premature menopause (MONDO:0001119)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004599_194	Mean platelet volume	1.000000e-11
GCST010703_222	Brain morphology (MOSTest)	6.000000e-13
GCST90002402_144	Platelet count	7.000000e-13
GCST90013407_132	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-34

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004309	platelet count
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500

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	increases expression, increases methylation	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
cobaltous chloride	increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects expression	2
Benzo(a)pyrene	affects methylation	2
Nickel	increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
arsenite	decreases reaction, affects binding	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
rutecarpine	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
ICG 001	increases expression	1
Acetaminophen	increases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists