SKIL

Summary

SKIL (SKI like proto-oncogene, HGNC:10897) is a protein-coding gene on chromosome 3q26.2, encoding Ski-like protein (P12757). May have regulatory role in cell division or differentiation in response to extracellular signals.

The protein encoded by this gene is a component of the SMAD pathway, which regulates cell growth and differentiation through transforming growth factor-beta (TGFB). In the absence of ligand, the encoded protein binds to the promoter region of TGFB-responsive genes and recruits a nuclear repressor complex. TGFB signaling causes SMAD3 to enter the nucleus and degrade this protein, allowing these genes to be activated. Four transcript variants encoding three different isoforms have been found for this gene.

Source: NCBI Gene 6498 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 96 total
• Transcription factor: yes — 23 downstream targets (CollecTRI)
• MANE Select transcript: NM_005414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10897
Approved symbol	SKIL
Name	SKI like proto-oncogene
Location	3q26.2
Locus type	gene with protein product
Status	Approved
Aliases	SNO, SnoN, SnoA
Ensembl gene	ENSG00000136603
Ensembl biotype	protein_coding
OMIM	165340
Entrez	6498

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000259119, ENST00000413427, ENST00000426052, ENST00000458537, ENST00000465590, ENST00000470571, ENST00000476188, ENST00000477216, ENST00000490894, ENST00000490989, ENST00000909215, ENST00000928164, ENST00000928165

RefSeq mRNA: 4 — MANE Select: NM_005414 NM_001145097, NM_001145098, NM_001248008, NM_005414

CCDS: CCDS33890, CCDS46953, CCDS46954

Canonical transcript exons

ENST00000259119 — 7 exons

Exon	Start	End
ENSE00001214279	170359699	170361429
ENSE00001832843	170357715	170357763
ENSE00003997999	170391036	170391260
ENSE00003998000	170390223	170390464
ENSE00003998001	170381244	170381341
ENSE00003998002	170384533	170384765
ENSE00003998003	170392259	170396835

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 98.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.6388 / max 988.5076, expressed in 1786 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39724	29.0272	1775
39727	2.5128	578
39723	0.8688	538
39722	0.6883	350
39725	0.6557	315
39721	0.5866	308
39720	0.4147	192
39726	0.2981	109
39731	0.2083	82
39728	0.2000	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	98.53	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.27	gold quality
tendon	UBERON:0000043	96.97	gold quality
jejunal mucosa	UBERON:0000399	96.88	gold quality
calcaneal tendon	UBERON:0003701	96.76	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.26	gold quality
visceral pleura	UBERON:0002401	94.94	gold quality
biceps brachii	UBERON:0001507	94.57	gold quality
jejunum	UBERON:0002115	94.53	gold quality
epithelium of nasopharynx	UBERON:0001951	94.48	gold quality
adrenal tissue	UBERON:0018303	94.44	gold quality
colonic epithelium	UBERON:0000397	94.25	gold quality
endothelial cell	CL:0000115	94.09	gold quality
superficial temporal artery	UBERON:0001614	93.84	gold quality
lower lobe of lung	UBERON:0008949	93.83	gold quality
pericardium	UBERON:0002407	93.68	gold quality
tonsil	UBERON:0002372	93.60	gold quality
bronchial epithelial cell	CL:0002328	93.47	gold quality
synovial joint	UBERON:0002217	93.47	gold quality
seminal vesicle	UBERON:0000998	92.79	gold quality
palpebral conjunctiva	UBERON:0001812	92.72	gold quality
tibia	UBERON:0000979	92.68	gold quality
eye	UBERON:0000970	92.31	gold quality
parietal pleura	UBERON:0002400	91.92	gold quality
pleura	UBERON:0000977	91.77	gold quality
gingival epithelium	UBERON:0001949	91.75	gold quality
duodenum	UBERON:0002114	91.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.23	gold quality
pigmented layer of retina	UBERON:0001782	91.09	gold quality
retina	UBERON:0000966	91.07	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	1975.67
E-GEOD-76312	yes	1102.29
E-MTAB-6678	yes	4.64
E-CURD-10	no	1576.72
E-CURD-112	no	2.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

23 targets.

Target	Regulation
ADAM12	Repression
AFP
CAV1
CD74
CDKN1A	Repression
DACH1
DCN
ESR1
FSHB	Repression
GADD45G
HGF
HSPA8
IGFBP7
IL4
MAP3K14
MYC	Repression
MYOG	Repression
SERPINE1	Repression
SKIL	Repression
SMAD7	Repression
TBXT
TH
TP53

Upstream regulators (CollecTRI, top): CREB1, ESR1, SKIL, SMAD4, SP1

miRNA regulators (miRDB)

276 targeting SKIL, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
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-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 40)

• the ability of Ski and SnoN to repress the growth inhibitory function of the Smad proteins is required for their transforming activity. (PMID:12764135)
• SnoN acts as a positive mediator of TGF-beta-induced transcription and cell cycle arrest in lung epithelial cells (PMID:15677458)
• Sno expression was identified as an important mechanism to shut off antiproliferative TGF-beta signaling in malignant melanoma (PMID:15809735)
• mechanism of regulation of TGF-beta signaling via differential subcellular localization of SnoN (PMID:16109768)
• A novel role of SnoN in the transforming activity of TGF-beta in fibroblasts was demonstrated. (PMID:16314499)
• SnoN also seems to regulate negatively the TGF-beta-responsive SMAD, mothers against DPP homolog 7 gene by binding and repressing its promoter in a similar way to Ski (PMID:16442497)
• SnoN is directly regulated by sumoylation leading to the enhancement of the ability of SnoN to repress transcription in a promoter-specific manner (PMID:16966324)
• snoN protein has both oncogenic and tumor suppressive properties in colorectal tumorigenesis. (PMID:17062133)
• SnoN plays both pro-tumorigenic and antitumorigenic roles at different stages of mammalian malignant progression (PMID:17074815)
• These results indicate that impaired competition with p300 is the possible cause of dysfunction of c-Ski/SnoN in scleroderma fibroblasts and that this might contribute to maintenance of the autocrine TGFbeta loop in this disease. (PMID:17469184)
• Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. (PMID:17510063)
• Results show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN. (PMID:17591695)
• CREB activation, in concert with Sp1, constitutes a molecular switch that confers the cell type-specific induction of SnoN in response to HGF stimulation (PMID:17625116)
• Ski and SnoN proteins are overexpressed in Barrett’s esophagus (PMID:18261624)
• SnoN overexpression is associated with depth of invasion and recurrence in patients with esophageal squamous cell carcinoma. (PMID:18612694)
• c-Ski and SnoN, mediators in TGF-beta resistance, might be implicated in melanoma growth and progression. (PMID:18782659)
• SnoN and Ski were overexpressed both in adenomas with severe dysplasia and colorectal carcinomas. (PMID:19096149)
• Data show that dominant-negative transforming growth factor beta type II receptor decreases matrix metalloproteinase 2 in hepatic stellate cells, and upregulates SKI-like oncogene, which antagonizes TGF-beta signaling. (PMID:19189315)
• results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells (PMID:19383336)
• SnoN is involved in differentiation in normal skin and benign and nonmetastatic skin tumors, but plays a proto-oncogenic role in undifferentiated squamous cell carcinoma (PMID:19538364)
• Regulation of TGF-beta-co-repressor (SnoN) is greatly affected suggesting that SnoN as a cardinal player in cholestasis-induced fibrogenesis. (PMID:19889106)
• Inhibition of Smad signaling may be achieved at the transcriptional level through c-Ski/receptor-Smad/co-mediator Smad4 interactions–REVIEW (PMID:19898560)
• BMP-7 prevents TGF-beta-mediated loss of the transcriptional repressor SnoN and hence specifically limits Smad3 DNA binding. (PMID:20093492)
• The endogenous SnoN plays a role in regulating ADAM12 expression in response to TGFbeta1. (PMID:20457602)
• SnoN elevation is associated with mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis. (PMID:20460516)
• The flexibility in the putative protein binding groove enables SnoN to recognize multiple interaction partners. (PMID:20957027)
• SnoN level promotes ERalpha signaling and possibly breast cancer progression. (PMID:22227247)
• the SNON-SMAD4 complex negatively regulated basal SKIL gene expression through binding the promoter and recruiting histone deacetylases (PMID:22674574)
• SnoN may have broad functions in the embryonic development and tissue morphogenesis [Review] (PMID:22710172)
• analysis of SnoN signaling in proliferating cells and postmitotic neurons [review] (PMID:22710173)
• SnoN mediates a negative feedback mechanism evoked by TGF-beta to inhibit BMP signaling and, subsequently, hypertrophic maturation of chondrocytes. (PMID:22767605)
• These results support our observation that cancer tissues have lower expression levels of SnoN, miR-720, and miR-1274A compared to adjacent normal tissues from esophageal squamous cell carcinoma patients. (PMID:23154181)
• SNON predominantly associates with SMAD2 at the promoters of primitive streak (PS) and early DE marker genes (PMID:23154981)
• Data suggest that SKIL expression is modulated by antineoplastic agents and may be involved in drug resistance in ovarian carcinoma; up-regulation of SKIL expression by arsenic trioxide and reduction of apoptosis involves activation of PI3K pathway. (PMID:23178716)
• These data strongly suggest that SnoN can function as a tumor suppressor at early stages of tumorigenesis in human cancer tissues. (PMID:23418461)
• SnoNspecific siRNA is capable of effectively inhibiting the expression of SnoN in human HepG2 cells, and the downregulation of SnoN expression induces growth inhibition and apoptosis (PMID:23446947)
• Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells. (PMID:23621864)
• these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain. (PMID:23764425)
• High SnoN expression is associated with metastasis in breast cancer. (PMID:23832742)
• The results indicate that protein ubiquitination promotes megakaryopoiesis via degrading SnoN, an inhibitor of CD61 expression, strengths the roles of ubiquitination in cellular differentiation. (PMID:24637302)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	skilb	ENSDARG00000022904
danio_rerio	skila	ENSDARG00000023933
mus_musculus	Skil	ENSMUSG00000027660
rattus_norvegicus	Skil	ENSRNOG00000009899

Paralogs (3): SKI (ENSG00000157933), SKOR1 (ENSG00000188779), SKOR2 (ENSG00000215474)

Protein

Protein identifiers

Ski-like protein — P12757 (reviewed: P12757)

Alternative names: Ski-related oncogene, Ski-related protein

All UniProt accessions (3): C9J8R9, P12757, H7C4V3

UniProt curated annotations — full annotation on UniProt →

Function. May have regulatory role in cell division or differentiation in response to extracellular signals.

Subunit / interactions. Interacts with CPNE4 (via VWFA domain). Interacts with SMAD2, SMAD3 and RNF111. Isoform 1 interacts with WWP1.

Tissue specificity. Isoform SNON and isoform SNOA are widely expressed. Highest expression is found in skeletal muscle, followed by placenta and lung. Lowest expression in heart, brain and pancreas. Isoform SNOI expression is restricted to skeletal muscle.

Post-translational modifications. Ubiquitinated by RNF111 and ARK2C, promoting proteasomal degradation, leading to enhance the BMP-Smad signaling.

Similarity. Belongs to the SKI family.

Isoforms (5)

UniProt ID	Names	Canonical?
P12757-1	SNON	yes
P12757-2	SNOA
P12757-3	SNON2
P12757-4	SNOI
P12757-5	5

RefSeq proteins (4): NP_001138569, NP_001138570, NP_001234937, NP_005405* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003380	SKI/SNO/DAC	Domain
IPR009061	DNA-bd_dom_put_sf	Homologous_superfamily
IPR010919	SAND-like_dom_sf	Homologous_superfamily
IPR014890	c-SKI_SMAD4-bd_dom	Domain
IPR023216	Tscrpt_reg_SKI_SnoN	Family
IPR037000	Ski_DNA-bd_sf	Homologous_superfamily

Pfam: PF02437, PF08782

UniProt features (37 total): helix 10, strand 9, splice variant 6, cross-link 4, turn 2, chain 1, region of interest 1, sequence variant 1, sequence conflict 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3EQ5	X-RAY DIFFRACTION	2.45
5C4V	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12757-F1	66.28	0.37

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 (5): 452, 50, 70, 489, 527

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 528 (showing top): GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GCANCTGNY_MYOD_Q6, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_MALE_GAMETE_GENERATION, GOBP_BLASTOCYST_FORMATION

GO Biological Process (22): negative regulation of transcription by RNA polymerase II (GO:0000122), blastocyst formation (GO:0001825), lymphocyte homeostasis (GO:0002260), transforming growth factor beta receptor signaling pathway (GO:0007179), spermatogenesis (GO:0007283), skeletal muscle tissue development (GO:0007519), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), response to cytokine (GO:0034097), negative regulation of cell differentiation (GO:0045596), response to antibiotic (GO:0046677), positive regulation of axonogenesis (GO:0050772), regulation of cell cycle (GO:0051726), muscle structure development (GO:0061061), lens fiber cell differentiation (GO:0070306), response to growth factor (GO:0070848), positive regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902043), positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage (GO:1902231), cell differentiation (GO:0030154), regulation of neurogenesis (GO:0050767)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), chromatin binding (GO:0003682), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), SMAD binding (GO:0046332), protein binding (GO:0005515)

GO Cellular Component (7): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), PML body (GO:0016605), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
Signaling by TGFB family members	1
RNA Polymerase II Transcription	1
Signaling by TGF-beta Receptor Complex	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
binding	3
protein binding	3
regulation of transcription by RNA polymerase II	2
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blastocyst development	1
anatomical structure formation involved in morphogenesis	1
leukocyte homeostasis	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
developmental process involved in reproduction	1
male gamete generation	1
striated muscle tissue development	1
skeletal muscle organ development	1
extrinsic apoptotic signaling pathway	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
response to peptide	1
cell differentiation	1
regulation of cell differentiation	1
negative regulation of cellular process	1
negative regulation of developmental process	1
response to chemical	1
axonogenesis	1
positive regulation of cell projection organization	1
positive regulation of neurogenesis	1
regulation of axonogenesis	1
cell cycle	1
regulation of cellular process	1
anatomical structure development	1
lens development in camera-type eye	1
epithelial cell differentiation	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

152 interactions, top by confidence:

A	B	Type	Score
SMAD4	SKI	psi-mi:“MI:0914”(association)	0.940
SMAD4	SMAD9	psi-mi:“MI:0914”(association)	0.750
SMAD4	SKIL	psi-mi:“MI:0915”(physical association)	0.740
NEFL	SKIL	psi-mi:“MI:0915”(physical association)	0.720
SKIL	NEFL	psi-mi:“MI:0915”(physical association)	0.720
VPS28	SKIL	psi-mi:“MI:0915”(physical association)	0.670
SKIL	VPS28	psi-mi:“MI:0915”(physical association)	0.670
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
OIP5	SKIL	psi-mi:“MI:0915”(physical association)	0.560
STK16	SKIL	psi-mi:“MI:0915”(physical association)	0.560
TLE5	SKIL	psi-mi:“MI:0915”(physical association)	0.560
SKIL	VPS28	psi-mi:“MI:0915”(physical association)	0.560
NXF3	SKIL	psi-mi:“MI:0915”(physical association)	0.560
SKIL	DRG1	psi-mi:“MI:0915”(physical association)	0.560
SKIL	OIP5	psi-mi:“MI:0915”(physical association)	0.560
SKIL	STK16	psi-mi:“MI:0915”(physical association)	0.560
VPS28	SKIL	psi-mi:“MI:0915”(physical association)	0.560
SKIL	NXF3	psi-mi:“MI:0915”(physical association)	0.560
DRG1	SKIL	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (177): SKIL (Two-hybrid), SKIL (Two-hybrid), STK16 (Two-hybrid), OIP5 (Two-hybrid), VPS28 (Two-hybrid), NXF3 (Two-hybrid), SMAD3 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western), SKIL (Affinity Capture-Western), PML (Affinity Capture-Western), SKIL (Two-hybrid), SKIL (Affinity Capture-MS), SKIL (Two-hybrid), SKIL (Two-hybrid), SKIL (Two-hybrid)

ESM2 similar proteins: A0A0R4IXF6, A0JMR6, A5WW08, F4HRV8, O17482, O60934, O88974, O94988, P12757, P14629, P49021, P79457, Q08AW4, Q08D35, Q12789, Q28C33, Q2TB10, Q3B7T1, Q3UD82, Q3UWM4, Q498F0, Q5F363, Q5F3F2, Q5FWP4, Q5HYC2, Q5JSH3, Q5R431, Q5R7T9, Q5R9R1, Q5RGA4, Q5VVJ2, Q60665, Q63505, Q69Z66, Q6GQV7, Q6INA9, Q6NVE8, Q6P256, Q6ZMT4, Q8C5W4

Diamond homologs: A7M7C7, P12755, P12757, P17863, P49140, P84550, P84551, Q02225, Q1LXZ9, Q2VWA4, Q5R431, Q60665, Q60698, Q8BX46, Q9TUG2, Q925Q8, Q96NX9

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
RNF111	down-regulates	SKIL	ubiquitination
SKIL	down-regulates	SMAD1	binding
SKIL	down-regulates	SMAD1/4	binding
SKIL	“down-regulates activity”	SMAD2	binding
SMURF2	“down-regulates activity”	SKIL	ubiquitination
SKIL	“down-regulates activity”	SMAD4	binding
SMURF	“down-regulates activity”	SKIL	ubiquitination
SKIL	“down-regulates activity”	SMAD2/SMAD4	binding
SKIL	“down-regulates activity”	SMAD3/SMAD4	binding
FZR1	“down-regulates quantity by destabilization”	SKIL	binding
APC-c	“down-regulates quantity by destabilization”	SKIL	polyubiquitination
RNF111	“down-regulates quantity by destabilization”	SKIL	polyubiquitination
SKIL	down-regulates	SMAD5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 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
Downregulation of SMAD2/3:SMAD4 transcriptional activity	6	27.6×	3e-05
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	5	23.0×	2e-04
SUMOylation of intracellular receptors	5	21.0×	3e-04
SUMOylation of transcription cofactors	5	15.2×	8e-04
Signaling by TGF-beta Receptor Complex	5	12.5×	2e-03
SUMOylation of DNA damage response and repair proteins	5	9.2×	6e-03
Signaling by TGFB family members	6	8.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	5	15.9×	3e-03
cellular response to transforming growth factor beta stimulus	5	13.5×	6e-03
wound healing	5	11.2×	9e-03
transforming growth factor beta receptor signaling pathway	6	9.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1605 predictions. Top by Δscore:

Variant	Effect	Δscore
3:170357853:G:T	donor_gain	1.0000
3:170359838:G:GT	donor_gain	1.0000
3:170359839:A:T	donor_gain	1.0000
3:170381242:A:AG	acceptor_gain	1.0000
3:170381243:G:GG	acceptor_gain	1.0000
3:170381243:GACA:G	acceptor_gain	1.0000
3:170384521:ACTT:A	acceptor_gain	1.0000
3:170384522:C:G	acceptor_gain	1.0000
3:170384531:A:AG	acceptor_gain	1.0000
3:170384532:G:GG	acceptor_gain	1.0000
3:170384532:GCT:G	acceptor_gain	1.0000
3:170384532:GCTA:G	acceptor_gain	1.0000
3:170391029:A:AG	acceptor_gain	1.0000
3:170391030:TTACA:T	acceptor_loss	1.0000
3:170391031:TACAG:T	acceptor_loss	1.0000
3:170391033:CA:C	acceptor_loss	1.0000
3:170391034:AGGA:A	acceptor_loss	1.0000
3:170391035:GGAA:G	acceptor_gain	1.0000
3:170357906:G:GG	donor_gain	0.9900
3:170357910:G:GT	donor_gain	0.9900
3:170360537:T:G	donor_gain	0.9900
3:170381231:T:G	acceptor_gain	0.9900
3:170381238:CTGCA:C	acceptor_loss	0.9900
3:170381239:T:A	acceptor_gain	0.9900
3:170381239:TGCA:T	acceptor_loss	0.9900
3:170381240:GCAG:G	acceptor_loss	0.9900
3:170381241:CA:C	acceptor_loss	0.9900
3:170381242:AGAC:A	acceptor_loss	0.9900
3:170381243:GA:G	acceptor_gain	0.9900
3:170381243:GAC:G	acceptor_gain	0.9900

AlphaMissense

4492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:170360777:T:C	L149S	1.000
3:170360800:T:C	F157L	1.000
3:170360801:T:C	F157S	1.000
3:170360802:T:A	F157L	1.000
3:170360802:T:G	F157L	1.000
3:170360825:T:A	L165H	1.000
3:170360825:T:C	L165P	1.000
3:170360827:T:C	C166R	1.000
3:170360829:T:G	C166W	1.000
3:170360831:T:C	L167S	1.000
3:170360922:T:G	C197W	1.000
3:170360936:T:C	L202P	1.000
3:170360945:T:C	L205S	1.000
3:170360983:T:C	C218R	1.000
3:170360987:G:A	G219E	1.000
3:170360990:T:C	L220P	1.000
3:170360993:T:A	I221N	1.000
3:170361007:G:C	A226P	1.000
3:170361015:A:C	R228S	1.000
3:170361015:A:T	R228S	1.000
3:170361017:T:C	L229S	1.000
3:170361133:T:C	C268R	1.000
3:170361151:G:C	G274R	1.000
3:170361202:T:C	C291R	1.000
3:170361204:T:G	C291W	1.000
3:170361238:T:C	F303L	1.000
3:170361239:T:C	F303S	1.000
3:170361240:T:A	F303L	1.000
3:170361240:T:G	F303L	1.000
3:170361283:T:A	W318R	1.000

dbSNP variants (sampled 300 via entrez): RS1000055950 (3:170385165 A>C,G), RS1000072585 (3:170378979 T>A,C), RS1000124364 (3:170369293 C>G,T), RS1000148624 (3:170357013 G>A,T), RS1000162401 (3:170391264 A>G), RS1000225688 (3:170395054 A>G), RS1000281773 (3:170357959 C>T), RS1000399294 (3:170357745 G>A), RS1000409622 (3:170358653 G>A,C), RS1000551969 (3:170389439 G>A,T), RS1000666577 (3:170365704 C>A), RS1000746329 (3:170357818 G>A), RS1000754664 (3:170364126 G>A), RS1000830814 (3:170396475 T>C), RS1000843819 (3:170362078 G>A)

Disease associations

OMIM: gene MIM:165340 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001148_1	Prostate cancer	7.000000e-22
GCST003372_61	Glomerular filtration rate (creatinine)	4.000000e-08
GCST003401_7	Glomerular filtration rate in non diabetics (creatinine)	3.000000e-08
GCST008058_234	Estimated glomerular filtration rate	6.000000e-09
GCST90011899_114	Aspartate aminotransferase levels	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases reaction	4
Cisplatin	decreases expression, increases expression, affects expression, affects cotreatment	3
Tretinoin	increases expression	3
bisphenol A	decreases reaction, increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
Copper	affects binding, decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
lead acetate	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
nonylphenol	decreases reaction, increases expression	1
resorcinol	decreases expression	1
4-nonylphenol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-octylphenol	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer