SFN

Summary

SFN (stratifin, HGNC:10773) is a protein-coding gene on chromosome 1p36.11, encoding 14-3-3 protein sigma (P31947). Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.

This gene encodes a cell cycle checkpoint protein. The encoded protein binds to translation and initiation factors and functions as a regulator of mitotic translation. In response to DNA damage this protein plays a role in preventing DNA errors during mitosis.

Source: NCBI Gene 2810 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 31 total
• Druggable target: yes
• MANE Select transcript: NM_006142

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10773
Approved symbol	SFN
Name	stratifin
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	YWHAS
Ensembl gene	ENSG00000175793
Ensembl biotype	protein_coding
OMIM	601290
Entrez	2810

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000339276

RefSeq mRNA: 1 — MANE Select: NM_006142 NM_006142

CCDS: CCDS288

Canonical transcript exons

ENST00000339276 — 1 exons

Exon	Start	End
ENSE00001406083	26863149	26864456

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 70.9030 / max 3303.7883, expressed in 589 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1667	70.9030	589

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	99.99	gold quality
gingival epithelium	UBERON:0001949	99.98	gold quality
squamous epithelium	UBERON:0006914	99.98	gold quality
esophagus squamous epithelium	UBERON:0006920	99.98	gold quality
gingiva	UBERON:0001828	99.97	gold quality
hair follicle	UBERON:0002073	99.97	gold quality
pharyngeal mucosa	UBERON:0000355	99.96	gold quality
tongue squamous epithelium	UBERON:0006919	99.95	gold quality
nipple	UBERON:0002030	99.93	gold quality
mammalian vulva	UBERON:0000997	99.91	gold quality
upper leg skin	UBERON:0004262	99.91	gold quality
cervix epithelium	UBERON:0004801	99.91	gold quality
penis	UBERON:0000989	99.90	gold quality
skin of hip	UBERON:0001554	99.90	gold quality
oral cavity	UBERON:0000167	99.86	gold quality
body of tongue	UBERON:0011876	99.85	gold quality
periodontal ligament	UBERON:0008266	99.82	gold quality
lower esophagus mucosa	UBERON:0035834	99.82	gold quality
pancreatic ductal cell	CL:0002079	99.79	gold quality
upper arm skin	UBERON:0004263	99.75	gold quality
tongue	UBERON:0001723	99.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.68	gold quality
epithelium of nasopharynx	UBERON:0001951	99.67	gold quality
colonic mucosa	UBERON:0000317	99.64	gold quality
amniotic fluid	UBERON:0000173	99.60	gold quality
ileal mucosa	UBERON:0000331	99.60	gold quality
palpebral conjunctiva	UBERON:0001812	99.60	gold quality
superior surface of tongue	UBERON:0007371	99.52	gold quality
epithelium of esophagus	UBERON:0001976	99.48	gold quality
skin of abdomen	UBERON:0001416	99.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	9311.03
E-HCAD-1	yes	2229.61
E-MTAB-9841	yes	1371.38
E-MTAB-8410	yes	46.18
E-GEOD-125970	yes	17.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, DNMT1, DNMT3A, MBD2, TP53, TP63, YAP1

miRNA regulators (miRDB)

30 targeting SFN, 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-8485	100.00	77.57	4731
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-4723-3P	97.67	65.91	1017
HSA-MIR-562	97.66	65.63	698
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-6769B-3P	97.41	65.53	1036
HSA-MIR-3183	97.40	65.68	978
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-500B-3P	96.49	65.40	1087
HSA-MIR-4471	95.11	66.84	755

Literature-anchored findings (GeneRIF, showing 40)

• Stratifin was first identified as an epithelial cell antigen exclusively expressed in epithelia. the functional role of sfn in cell proliferation and apoptosis could be relevant to the regulation of growth and differentiation as a tumor suppressor gene (PMID:12582028)
• Protein 14-3-3sigma has a role as a negative regulator of the glucocorticoid signaling pathway (PMID:12730237)
• 14-3-3sigma (Sfn protein) expression was exclusively present in various epithelial cells and was stronger in cells destined for squamous epithelium or differentiating toward squamous cells in human normal and neoplastic cells (PMID:12787309)
• 14-3-3 sigma appears to have a positive feedback effect on p53 activity (PMID:14517281)
• These results suggest that 14-3-3 sigma plays a constitutive role in papillary carcinoma rather than acting as a cell cycle regulator, whereas it is not required for the occurrence and development of follicular tumor. (PMID:14568170)
• 14-3-3 sigma is inactivated mainly by aberrant DNA methylation and may play an important role in the pathogenesis of epithelial ovarian cancer (PMID:15102672)
• Data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. (PMID:15131044)
• a keratinocyte-releasable form of stratifin mimics the collagenase stimulatory effect of keratinocyte conditioned media for dermal fibroblasts. (PMID:15140222)
• These data suggest that 14-3-3sigma expression is down-regulated during the neoplastic transition of prostate epithelial cells. (PMID:15184053)
• 14-3-3sigma has a role in mediating IGF-I-induced cell cycle progression (PMID:15187095)
• The present immunohistochemical study confirmed 14-3-3sigma as a tumor suppressor in breast carcinogenesis. (PMID:15260850)
• Downdownregulation of 14-3-3 sigma mqy play critical roles in the neoplastic development and radiosensitivity of adenoid cystic carcinoma. (PMID:15292943)
• RACK1 physically associated with the p63alpha C-terminal domain through its WD40 domain. However, stratifin binds with phosphorylated DeltaNp63alpha in response to cisplatin. (PMID:15467455)
• In human cervical cancers, inactivation of either 14-3-3sigma or p16 has an effect equivalent to the expression of E6 and E7 oncoproteins of HPV. (PMID:15482563)
• downregulation of 14-3-3sigma expression in PCa suggests that it significantly contributes to the formation of prostate cancer, potentially by allowing the escape from a DNA damage-induced arrest elicited by telomere shortening (PMID:15489902)
• is induced in keratinocytes during exit from the stem cell compartment (PMID:15654940)
• keratinocytes express a high level of 14-3-3sigma at the levels of mRNA and protein. (PMID:15654971)
• analysis of sites determining 14-3-3sigma functional specificity (PMID:15731107)
• The 14-3-3sigma itself is subject to regulation by p53 upon DNA damage and by epigenetic deregulation and Gene silencing of 14-3-3sigma by CpG methylation has been found in many human cancer types. (PMID:15857577)
• The 14-3-3sigma is involved in cell-cycle control and prevents the accumulation of chromosomal damage. (PMID:15857578)
• Targeting 14-3-3sigma might be a new therapeutic strategy in colorectal carcinoma. (PMID:15867223)
• stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway (PMID:16098031)
• The p53-inducible gene 14-3-3sigma is a new example of a gene important to human cancer, where epigenetic mechanisms participate in the control of normal cell type-specific expression, as well as aberrant gene silencing in cancer cells. (PMID:16229802)
• Absence of 14-3-3sigma turned out to be statistically independent risk factor in disease-free survival and overall survival even in patients with early-stage disease. (PMID:16243811)
• 14-3-3 sigma expression inversely correlated with estrogen receptor alpha, progesterone receptor and estrogen-responsive finger protein, and positively correlated with myometrial invasion and lymph node metastasis in endometrial adenocarcinoma. (PMID:16271083)
• 14-3-3sigma plays the tumor-suppressive role in nasopharyngeal carcinoma cells. (PMID:16505098)
• 14-3-3sigma stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt (PMID:16532026)
• Expression level of 14-3-3sigma in androgen-independent prostate cancer cell lines DU145, PC3, and CWR22RV are much higher than that in the androgen-dependent cell line LNCaP. (PMID:16648560)
• the transcriptional silencing of the 14-3-3sigma gene is caused by promoter CpG island methylation associated with MBD2, which may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease (PMID:16786000)
• These observations suggest that 14-3-3sigma might serve as a marker of oxidative and DNA-damaging stresses inducing the mitotic checkpoint dysfunction in reactive astrocytes under pathological conditions. (PMID:16797759)
• Taken together, our present results strongly suggest that p73-dependent induction of 14-3-3sigma plays an important role in the regulation of chemo-sensitivity of breast cancers bearing p53 mutation. (PMID:16814250)
• p21WAF1/CIP1 and 14-3-3 sigma expression was several fold higher in degenerated aortic valves with no calcification versus degenerated aortic valves with calcification on both transcription and translation levels (PMID:16953367)
• The different patterns of aberrant methylation of the 14-3-3 sigma gene in the various histopathological cancer types of the urinary bladder point to a role in tumor cell differentiation. (PMID:16964403)
• Results suggest that an onocogenic role of overexpressed cyclin B1 is mainly mediated in nuclei of breast carcinoma cells, and the nuclear translocation is regulated by polo-like kinase 1 and 14-3-3sigma. (PMID:17359284)
• aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis (PMID:17361185)
• These results indicate that depressed 14-3-3sigma protein is involved in the uncontrolled cell cycle in intrahepatic cholangiocarcinoma and that the decreased expression of 14-3-3sigma protein is a significant indicator of poor prognosis (PMID:17391729)
• 14-3-3sigma isoform interacts with BP180 in keratinocytes. (PMID:17443672)
• 14-3-3sigma can enhance the transcriptional activity of p73 in a dose-dependent manner. (PMID:17672938)
• The present data suggest that promoter methylation of the 14-3-3 sigma and CAGE-1 genes plays a crucial role during the phenotypical morphogenesis of vesical adenocarcinomas including signet ring cell carcinomas by an epigenetic mechanism. (PMID:17786288)
• Methylation and intratumoural heterogeneity leading to inactivation of 14-3-3 sigma is associated with oral cancer (PMID:17786341)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ywhaqb	ENSDARG00000023323
danio_rerio	ywhaqa	ENSDARG00000042539
mus_musculus	Sfn	ENSMUSG00000047281
rattus_norvegicus	Sfnl1	ENSRNOG00000004188
drosophila_melanogaster	14-3-3zeta	FBGN0004907
caenorhabditis_elegans		WBGENE00001502
caenorhabditis_elegans		WBGENE00003920

Paralogs (6): YWHAE (ENSG00000108953), YWHAH (ENSG00000128245), YWHAQ (ENSG00000134308), YWHAZ (ENSG00000164924), YWHAB (ENSG00000166913), YWHAG (ENSG00000170027)

Protein

Protein identifiers

14-3-3 protein sigma — P31947 (reviewed: P31947)

Alternative names: Epithelial cell marker protein 1, Stratifin

All UniProt accessions (1): P31947

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Promotes cytosolic retention of GBP1 GTPase by binding to phosphorylated GBP1, thereby inhibiting the innate immune response. Also acts as a TP53/p53-regulated inhibitor of G2/M progression. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway. Acts to maintain desmosome cell junction adhesion in epithelial cells via interacting with and sequestering PKP3 to the cytoplasm, thereby restricting its translocation to existing desmosome structures and therefore maintaining desmosome protein homeostasis. Also acts to facilitate PKP3 exchange at desmosome plaques, thereby maintaining keratinocyte intercellular adhesion. May also regulate MDM2 autoubiquitination and degradation and thereby activate p53/TP53.

Subunit / interactions. Homodimer. Interacts with KRT17 and SAMSN1. Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29 and VPS35. Interacts with GAB2. Interacts with SRPK2. Interacts with COPS6. Interacts with COP1; this interaction leads to proteasomal degradation. Interacts with the ‘Thr-369’ phosphorylated form of DAPK2. Interacts with PI4KB. Interacts with SLITRK1. Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation. Interacts with PKP3 (via N-terminus); the interaction maintains the cytoplasmic pool of PKP3, facilitates PKP3 exchange at desmosomes and restricts PKP3 localization to existing desmosome cell junctions. Interacts with LCP2.

Subcellular location. Cytoplasm. Nucleus. Secreted.

Tissue specificity. Present mainly in tissues enriched in stratified squamous keratinizing epithelium.

Post-translational modifications. Ubiquitinated. Ubiquitination by RFFL induces proteasomal degradation and indirectly regulates p53/TP53 activation.

Similarity. Belongs to the 14-3-3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P31947-1	1	yes
P31947-2	2

RefSeq proteins (1): NP_006133* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000308	14-3-3	Family
IPR023409	14-3-3_CS	Conserved_site
IPR023410	14-3-3_domain	Domain
IPR036815	14-3-3_dom_sf	Homologous_superfamily
IPR037435	14-3-3_sigma	Family

Pfam: PF00244

UniProt features (24 total): helix 12, sequence conflict 3, modified residue 3, site 2, chain 1, strand 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

524 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3IQU	X-RAY DIFFRACTION	1.05
7AZ2	X-RAY DIFFRACTION	1.08
6HMT	X-RAY DIFFRACTION	1.1
7BAA	X-RAY DIFFRACTION	1.1
8BZC	X-RAY DIFFRACTION	1.1
8BZW	X-RAY DIFFRACTION	1.1
8C04	X-RAY DIFFRACTION	1.1
9GG8	X-RAY DIFFRACTION	1.1
8ANC	X-RAY DIFFRACTION	1.11
6Y1J	X-RAY DIFFRACTION	1.13
6G6X	X-RAY DIFFRACTION	1.13
6NV2	X-RAY DIFFRACTION	1.13
3IQJ	X-RAY DIFFRACTION	1.15
3MHR	X-RAY DIFFRACTION	1.15
7AZ1	X-RAY DIFFRACTION	1.15
7B9R	X-RAY DIFFRACTION	1.15
7B9T	X-RAY DIFFRACTION	1.15
7NFW	X-RAY DIFFRACTION	1.19
3IQV	X-RAY DIFFRACTION	1.2
5MHC	X-RAY DIFFRACTION	1.2
5MXO	X-RAY DIFFRACTION	1.2
6HMU	X-RAY DIFFRACTION	1.2
6QHL	X-RAY DIFFRACTION	1.2
6RHC	X-RAY DIFFRACTION	1.2
7AEW	X-RAY DIFFRACTION	1.2
7BA8	X-RAY DIFFRACTION	1.2
7BI3	X-RAY DIFFRACTION	1.2
7BIQ	X-RAY DIFFRACTION	1.2
7BIW	X-RAY DIFFRACTION	1.2
7NV4	X-RAY DIFFRACTION	1.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31947-F1	93.27	0.86

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): 56 (interaction with phosphoserine on interacting protein); 129 (interaction with phosphoserine on interacting protein)

Post-translational modifications (3): 5, 74, 248

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-111447	Activation of BAD and translocation to mitochondria
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-6804114	TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
R-HSA-75035	Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex
R-HSA-9614399	Regulation of localization of FOXO transcription factors
R-HSA-9735871	SARS-CoV-1 targets host intracellular signalling and regulatory pathways
R-HSA-9755779	SARS-CoV-2 targets host intracellular signalling and regulatory pathways
R-HSA-9968551	Regulation of GBP-mediated host defense
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-199991	Membrane Trafficking
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5357801	Programmed Cell Death
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-6791312	TP53 Regulates Transcription of Cell Cycle Genes
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 420 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, CCAWYNNGAAR_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, JAEGER_METASTASIS_DN, GOBP_KERATINOCYTE_PROLIFERATION, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN

GO Biological Process (31): negative regulation of transcription by RNA polymerase II (GO:0000122), release of cytochrome c from mitochondria (GO:0001836), keratinocyte development (GO:0003334), negative regulation of protein kinase activity (GO:0006469), protein export from nucleus (GO:0006611), signal transduction (GO:0007165), intracellular protein localization (GO:0008104), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), regulation of epidermal cell division (GO:0010482), negative regulation of keratinocyte proliferation (GO:0010839), regulation of cell-cell adhesion (GO:0022407), positive regulation of cell growth (GO:0030307), keratinization (GO:0031424), regulation of protein localization (GO:0032880), keratinocyte proliferation (GO:0043616), positive regulation of epidermal cell differentiation (GO:0045606), positive regulation of cell adhesion (GO:0045785), negative regulation of innate immune response (GO:0045824), positive regulation of protein export from nucleus (GO:0046827), regulation of cell cycle (GO:0051726), establishment of skin barrier (GO:0061436), stem cell proliferation (GO:0072089), cAMP/PKA signal transduction (GO:0141156), negative regulation of protein localization to plasma membrane (GO:1903077), positive regulation of protein localization (GO:1903829), negative regulation of stem cell proliferation (GO:2000647), keratinocyte differentiation (GO:0030216), defense response to bacterium (GO:0042742), skin development (GO:0043588), cytolysis in another organism (GO:0051715), non-canonical inflammasome complex assembly (GO:0160075)

GO Molecular Function (8): protein kinase C inhibitor activity (GO:0008426), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), cadherin binding (GO:0045296), phosphoserine residue binding (GO:0050815), protein sequestering activity (GO:0140311), protein binding (GO:0005515), phosphoprotein binding (GO:0051219)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Activation of BH3-only proteins	1
Membrane Trafficking	1
RHO GTPase Effectors	1
Transcriptional Regulation by TP53	1
TP53 Regulates Transcription of Cell Cycle Genes	1
G2/M DNA damage checkpoint	1
FOXO-mediated transcription	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
GBP-mediated host defense	1
Programmed Cell Death	1
Apoptosis	1
Intrinsic Pathway for Apoptosis	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	3
keratinocyte differentiation	2
regulation of cellular process	2
regulation of cell adhesion	2
positive regulation of cellular process	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
apoptotic mitochondrial changes	1
apoptotic signaling pathway	1
epithelial cell development	1
negative regulation of protein phosphorylation	1
protein kinase activity	1
negative regulation of kinase activity	1
regulation of protein kinase activity	1
intracellular protein transport	1
nuclear export	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
macromolecule localization	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
epidermal cell division	1
regulation of cell division	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
cell-cell adhesion	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
multicellular organismal process	1
intracellular protein localization	1
regulation of localization	1
epithelial cell proliferation	1
epidermal cell differentiation	1
positive regulation of epithelial cell differentiation	1

Protein interactions and networks

STRING

4059 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SFN	KRT17	Q04695	951
SFN	CDK2	P24941	934
SFN	CDC25C	P30307	883
SFN	TP53	P04637	859
SFN	CDK4	P11802	846
SFN	ESR1	P03372	846
SFN	TXNDC9	O14530	845
SFN	MDM2	Q00987	800
SFN	TRIM25	Q14258	754
SFN	AKT1	P31749	731
SFN	ANPEP	P15144	712
SFN	SERPINB5	P36952	657
SFN	CCNB1	P14635	644
SFN	GADD45A	P24522	610
SFN	PKP3	Q9Y446	596

IntAct

562 interactions, top by confidence:

A	B	Type	Score
SFN	BAD	psi-mi:“MI:0915”(physical association)	0.910
SFN	RAF1	psi-mi:“MI:0407”(direct interaction)	0.890
SFN	RAF1	psi-mi:“MI:0915”(physical association)	0.890
EGFR	SFN	psi-mi:“MI:0915”(physical association)	0.830
EGFR	GAPDH	psi-mi:“MI:0914”(association)	0.790
SFN	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.780
SFN	SFN	psi-mi:“MI:0915”(physical association)	0.760
SFN	ARAF	psi-mi:“MI:0915”(physical association)	0.760
SFN	MAPT	psi-mi:“MI:0407”(direct interaction)	0.750
JADE1	KAT7	psi-mi:“MI:0914”(association)	0.720
COP1	SFN	psi-mi:“MI:0915”(physical association)	0.720
SFN	COP1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HDAC7	SFN	psi-mi:“MI:0915”(physical association)	0.690
SFN	TNK1	psi-mi:“MI:0915”(physical association)	0.690
SFN	FOXO4	psi-mi:“MI:0915”(physical association)	0.680
FOXO4	SFN	psi-mi:“MI:0915”(physical association)	0.680

BioGRID (931): SFN (Affinity Capture-Western), DTL (Affinity Capture-Western), SFN (Two-hybrid), MAGEA1 (Two-hybrid), FOXO4 (Two-hybrid), MKRN3 (Two-hybrid), FAM53C (Two-hybrid), ZC2HC1C (Two-hybrid), CCDC102B (Two-hybrid), LONRF1 (Two-hybrid), RAB3IP (Two-hybrid), FAM9B (Two-hybrid), SFN (Affinity Capture-Western), SFN (Affinity Capture-Western), AKT1 (Affinity Capture-Western)

ESM2 similar proteins: A1Z6M6, A7RL75, A8E7I5, A8XHX1, C4NYP8, D4A6D7, O13754, O14217, O42668, O76094, O77642, O96436, P23231, P31947, P33731, P68509, P68511, Q03560, Q04917, Q0VC36, Q12118, Q13217, Q20683, Q24902, Q25538, Q27968, Q2M021, Q32NU8, Q5EBF2, Q5R8D8, Q5U2X2, Q5ZI13, Q6CFJ0, Q6ES52, Q7ZU45, Q86DS1, Q8C0S4, Q8CC21, Q8MM75, Q8MUA4

Diamond homologs: A4K2U9, B8NLM9, O49995, O49998, O65352, O70456, O77642, P27348, P29309, P29310, P29311, P29361, P31946, P31947, P34730, P35213, P41932, P42643, P42644, P42652, P42653, P42654, P42656, P48348, P49106, P52908, P54632, P61981, P61982, P61983, P62258, P62259, P62260, P62261, P62262, P63101, P63102, P63103, P63104, P68250

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
MAPK10	down-regulates	SFN	phosphorylation
MAPK8	down-regulates	SFN	phosphorylation
MAPK9	down-regulates	SFN	phosphorylation
SFN	down-regulates	SNAI1	relocalization
JNK	down-regulates	SFN	phosphorylation
verteporfin	“up-regulates quantity”	SFN	“chemical activation”
SFN	“down-regulates activity”	YAP1	relocalization
TRIM25	“down-regulates quantity by destabilization”	SFN	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 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	7	52.8×	5e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	46.6×	1e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	39.9×	6e-07
Activation of BH3-only proteins	7	34.4×	1e-07
Signaling by ERBB2 ECD mutants	5	33.3×	1e-05
RHO GTPases activate PKNs	9	28.3×	5e-09
SHC1 events in ERBB2 signaling	5	23.6×	5e-05
Signaling by ERBB2 TMD/JMD mutants	5	23.6×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
insulin-like growth factor receptor signaling pathway	5	18.5×	1e-03
positive regulation of substrate adhesion-dependent cell spreading	5	14.0×	3e-03
MAPK cascade	12	13.7×	3e-08
protein targeting	5	13.7×	3e-03
protein phosphorylation	26	13.2×	7e-19
ERK1 and ERK2 cascade	5	11.9×	5e-03
epidermal growth factor receptor signaling pathway	6	11.1×	2e-03
positive regulation of protein localization to plasma membrane	5	10.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

61 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26863956:C:G	donor_gain	0.6900
1:26863669:G:GT	donor_gain	0.6800
1:26863590:C:G	donor_gain	0.6200
1:26863755:CG:C	acceptor_gain	0.6000
1:26863689:G:GT	donor_gain	0.5900
1:26863658:C:A	donor_gain	0.5800
1:26863921:G:T	donor_gain	0.5500
1:26863693:G:GT	donor_gain	0.5400
1:26863752:CTACG:C	acceptor_gain	0.5400
1:26863755:C:CA	acceptor_gain	0.5300
1:26863651:GCCCG:G	donor_gain	0.5200
1:26863650:AGCCC:A	donor_gain	0.4900
1:26863777:G:GT	donor_gain	0.4700
1:26863921:G:GT	donor_gain	0.4700
1:26863843:G:GT	donor_gain	0.4600
1:26863694:A:T	donor_gain	0.4500
1:26863614:G:GA	donor_gain	0.4300
1:26863632:G:GT	donor_gain	0.4000
1:26863756:G:GC	acceptor_gain	0.4000
1:26863751:ACTAC:A	acceptor_gain	0.3800
1:26863613:T:TA	donor_gain	0.3700
1:26863753:TACG:T	acceptor_gain	0.3600
1:26863754:ACGA:A	acceptor_gain	0.3600
1:26863755:C:G	acceptor_gain	0.3600
1:26863654:C:CA	donor_gain	0.3500
1:26863754:AC:A	acceptor_gain	0.3500
1:26864074:GGC:G	donor_gain	0.3400
1:26863751:A:AG	acceptor_gain	0.3300
1:26863955:GC:G	donor_gain	0.3300
1:26863660:GCC:G	donor_gain	0.3100

AlphaMissense

1628 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26863357:A:G	K49E	1.000
1:26863358:A:T	K49M	1.000
1:26863359:G:C	K49N	1.000
1:26863359:G:T	K49N	1.000
1:26863567:T:C	F119L	1.000
1:26863569:C:A	F119L	1.000
1:26863569:C:G	F119L	1.000
1:26863588:G:C	D126H	1.000
1:26863589:A:C	D126A	1.000
1:26863589:A:G	D126G	1.000
1:26863589:A:T	D126V	1.000
1:26863590:C:A	D126E	1.000
1:26863590:C:G	D126E	1.000
1:26863733:T:C	L174P	1.000
1:26863735:A:G	N175D	1.000
1:26863737:C:A	N175K	1.000
1:26863737:C:G	N175K	1.000
1:26863877:T:C	L222P	1.000
1:26863357:A:C	K49Q	0.999
1:26863358:A:C	K49T	0.999
1:26863379:G:T	R56M	0.999
1:26863380:G:C	R56S	0.999
1:26863380:G:T	R56S	0.999
1:26863576:A:G	K122E	0.999
1:26863578:G:C	K122N	0.999
1:26863578:G:T	K122N	0.999
1:26863585:G:C	G125R	0.999
1:26863586:G:A	G125D	0.999
1:26863597:C:A	R129S	0.999
1:26863598:G:C	R129P	0.999

dbSNP variants (sampled 300 via entrez): RS1001337743 (1:26864216 G>A), RS1001873781 (1:26864664 T>C), RS1002119940 (1:26864844 G>A), RS1002472348 (1:26864571 T>C), RS1003058604 (1:26862841 G>C,T), RS1003414566 (1:26862169 C>T), RS1005954729 (1:26862987 C>T), RS1005988083 (1:26864936 A>G), RS1007025492 (1:26864023 TG>T), RS1007419604 (1:26861630 G>T), RS1007639459 (1:26862128 G>A), RS1008070828 (1:26861360 T>C), RS1010096102 (1:26863713 C>T), RS1011768407 (1:26861689 T>C), RS1011829366 (1:26862600 C>T)

Disease associations

OMIM: gene MIM:601290 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004623_145	Neutrophil percentage of granulocytes	1.000000e-09
GCST004631_49	Basophil percentage of white cells	3.000000e-12
GCST004634_33	Basophil percentage of granulocytes	5.000000e-14
GCST007611_16	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	6.000000e-12
GCST90002382_66	Eosinophil percentage of white cells	6.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007994	neutrophil percentage of granulocytes
EFO:0007992	basophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1909482 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 8 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.52	Kd	3.058	nM	CHEMBL3752910
8.52	ED50	3.058	nM	CHEMBL3752910
5.58	IC50	2600	nM	CHEMBL4243744
5.58	IC50	2600	nM	CHEMBL4237531
5.58	IC50	2600	nM	CHEMBL4247540
5.58	IC50	2600	nM	CHEMBL4240436
5.58	IC50	2600	nM	CHEMBL4250552
5.30	IC50	5000	nM	CHEMBL3813927

PubChem BioAssay actives

7 with measured affinity, of 31 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149934: Binding affinity to human SFN incubated for 45 mins by Kinobead based pull down assay	kd	0.0031	uM
[(2S)-3-(1,3-benzodioxol-5-ylmethylamino)-2-[[2-[[4-(chloromethyl)benzoyl]amino]acetyl]amino]-3-oxopropyl] dihydrogen phosphate	1393198: Inhibition of TMR-GG-RLSHpSSLPG-NH2 binding to recombinant human GST-tagged 14-3-3-sigma preincubated for 30 mins followed by TMR-GG-RLSHpSSLPG-NH2 addition and measured after 60 mins by fluorescence polarization assay	ic50	2.6000	uM
[(2S)-3-[2-(4-hydroxyphenyl)ethylamino]-2-(3-methylbut-2-enoylamino)-3-oxopropyl] dihydrogen phosphate	1393198: Inhibition of TMR-GG-RLSHpSSLPG-NH2 binding to recombinant human GST-tagged 14-3-3-sigma preincubated for 30 mins followed by TMR-GG-RLSHpSSLPG-NH2 addition and measured after 60 mins by fluorescence polarization assay	ic50	2.6000	uM
[(2S)-2-[[2-[[4-(chloromethyl)benzoyl]amino]acetyl]amino]-3-[2-(4-hydroxyphenyl)ethylamino]-3-oxopropyl] dihydrogen phosphate	1393198: Inhibition of TMR-GG-RLSHpSSLPG-NH2 binding to recombinant human GST-tagged 14-3-3-sigma preincubated for 30 mins followed by TMR-GG-RLSHpSSLPG-NH2 addition and measured after 60 mins by fluorescence polarization assay	ic50	2.6000	uM
[(2S)-3-(1,3-benzodioxol-5-ylmethylamino)-2-(3-methylbut-2-enoylamino)-3-oxopropyl] dihydrogen phosphate	1393198: Inhibition of TMR-GG-RLSHpSSLPG-NH2 binding to recombinant human GST-tagged 14-3-3-sigma preincubated for 30 mins followed by TMR-GG-RLSHpSSLPG-NH2 addition and measured after 60 mins by fluorescence polarization assay	ic50	2.6000	uM
[(2S)-2-[[2-[(4-azidobenzoyl)amino]acetyl]amino]-3-[2-(4-hydroxyphenyl)ethylamino]-3-oxopropyl] dihydrogen phosphate	1393198: Inhibition of TMR-GG-RLSHpSSLPG-NH2 binding to recombinant human GST-tagged 14-3-3-sigma preincubated for 30 mins followed by TMR-GG-RLSHpSSLPG-NH2 addition and measured after 60 mins by fluorescence polarization assay	ic50	2.6000	uM
[2-[2-(2,3-dichloroanilino)-2-oxoethoxy]phenyl]phosphonic acid	1304826: Inhibition of 14-3-3sigma (unknown origin) assessed as reduction in 14-3-3sigma- mediated increase in MMP1 mRNA by cell based assay	ic50	5.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, increases expression, decreases methylation, increases mutagenesis	9
Valproic Acid	affects cotreatment, increases expression, affects expression	9
Cisplatin	increases expression, increases reaction, decreases expression, affects response to substance, affects cotreatment (+1 more)	7
sodium arsenite	decreases expression, increases expression	6
Fluorouracil	increases reaction, affects expression, increases expression, affects cotreatment, affects response to substance (+1 more)	5
Cyclosporine	increases expression	5
Aflatoxin B1	affects expression, increases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Acetaminophen	decreases expression, increases expression	3
Quercetin	increases expression	3
Cadmium Chloride	increases expression	3
bisphenol A	affects expression, increases expression	2
lead acetate	increases expression	2
potassium bromate	increases expression	2
ochratoxin A	decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Bortezomib	decreases expression, increases expression, affects cotreatment	2
Decitabine	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Gemcitabine	affects binding, decreases reaction, decreases methylation, increases expression, increases methylation (+6 more)	2
Dactinomycin	increases secretion, affects cotreatment, increases expression	2
Doxorubicin	decreases expression, increases expression, affects response to substance, affects reaction	2
Methotrexate	increases expression	2
Methyl Methanesulfonate	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
beta-Naphthoflavone	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1912841	Binding	Binding affinity to histidine-tagged human recombinant 14-3-3sigma by transferred NOESY analysis	Computational techniques are valuable tools for the discovery of protein-protein interaction inhibitors: the 14-3-3σ case. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2F5	Abcam HeLa SFN KO	Cancer cell line	Female
CVCL_HD94	HCT 116 SFN(-/-)	Cancer cell line	Male

Clinical trials (associated diseases)

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