ERRFI1

Summary

ERRFI1 (ERBB receptor feedback inhibitor 1, HGNC:18185) is a protein-coding gene on chromosome 1p36.23, encoding ERBB receptor feedback inhibitor 1 (Q9UJM3). Negative regulator of EGFR signaling in skin morphogenesis. In precision oncology, ERRFI1 E384* confers sensitivity to Erlotinib in Cholangiocarcinoma (CIViC Level C).

ERRFI1 is a cytoplasmic protein whose expression is upregulated with cell growth (Wick et al., 1995 [PubMed 7641805]). It shares significant homology with the protein product of rat gene-33, which is induced during cell stress and mediates cell signaling (Makkinje et al., 2000 [PubMed 10749885]; Fiorentino et al., 2000 [PubMed 11003669]).

Source: NCBI Gene 54206 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 67 total
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_018948

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18185
Approved symbol	ERRFI1
Name	ERBB receptor feedback inhibitor 1
Location	1p36.23
Locus type	gene with protein product
Status	Approved
Aliases	MIG-6, GENE-33, RALT
Ensembl gene	ENSG00000116285
Ensembl biotype	protein_coding
OMIM	608069
Entrez	54206

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 nonsense_mediated_decay

ENST00000377482, ENST00000467067, ENST00000469499, ENST00000474874, ENST00000487559, ENST00000857115, ENST00000857116, ENST00000857117, ENST00000857118, ENST00000857119, ENST00000857120, ENST00000857121, ENST00000857122, ENST00000857123, ENST00000857124, ENST00000963988, ENST00000963989

RefSeq mRNA: 1 — MANE Select: NM_018948 NM_018948

CCDS: CCDS94

Canonical transcript exons

ENST00000377482 — 4 exons

Exon	Start	End
ENSE00001151225	8015308	8015384
ENSE00001181132	8026158	8026309
ENSE00001474071	8011727	8014396
ENSE00002851188	8015495	8015692

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.4763 / max 866.0849, expressed in 1627 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10096	48.7555	1620
10092	0.7732	431
10091	0.5541	298
10089	0.4441	215
10087	0.2556	114
10090	0.2283	99
10094	0.1828	74
10093	0.1791	68
10088	0.1035	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.00	gold quality
vena cava	UBERON:0004087	98.86	gold quality
right lobe of liver	UBERON:0001114	98.63	gold quality
tibialis anterior	UBERON:0001385	98.57	gold quality
mucosa of stomach	UBERON:0001199	98.55	gold quality
tibial artery	UBERON:0007610	98.50	gold quality
popliteal artery	UBERON:0002250	98.49	gold quality
synovial joint	UBERON:0002217	98.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.22	gold quality
liver	UBERON:0002107	98.21	gold quality
left ovary	UBERON:0002119	98.21	gold quality
lower esophagus	UBERON:0013473	98.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.17	gold quality
aorta	UBERON:0000947	98.13	gold quality
cartilage tissue	UBERON:0002418	97.93	gold quality
pancreas	UBERON:0001264	97.90	gold quality
ascending aorta	UBERON:0001496	97.78	gold quality
thoracic aorta	UBERON:0001515	97.72	gold quality
right ovary	UBERON:0002118	97.59	gold quality
layer of synovial tissue	UBERON:0007616	97.54	gold quality
descending thoracic aorta	UBERON:0002345	97.52	gold quality
epithelial cell of pancreas	CL:0000083	97.50	gold quality
left uterine tube	UBERON:0001303	97.47	gold quality
gall bladder	UBERON:0002110	97.38	gold quality
left coronary artery	UBERON:0001626	97.31	gold quality
tibia	UBERON:0000979	97.15	gold quality
oviduct epithelium	UBERON:0004804	97.12	gold quality
coronary artery	UBERON:0001621	96.88	gold quality
omental fat pad	UBERON:0010414	96.88	gold quality
peritoneum	UBERON:0002358	96.87	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	2057.15
E-MTAB-8142	yes	90.98
E-CURD-119	yes	60.19
E-GEOD-135922	yes	50.88
E-MTAB-10287	yes	31.18
E-MTAB-10553	yes	22.93
E-HCAD-10	yes	13.83
E-CURD-112	yes	8.14
E-MTAB-9388	yes	6.31
E-GEOD-130148	yes	4.12
E-MTAB-7249	no	7525.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT1, HIF1A, NCOA1, PGR

miRNA regulators (miRDB)

127 targeting ERRFI1, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4668-3P	100.00	68.74	2635
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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754

Literature-anchored findings (GeneRIF, showing 40)

• MIG-6/RALT is a transcriptionally controlled inhibitor of mitogenic and transforming signals generated by the ErbB-2 oncogene. MIG-6/RALT forms a physical complex with activated ErbB-2 and co-localizes with ErbB-2 in living cells. (PMID:11003669)
• RALT is a transcriptionally controlled feedback inhibitor of ErbB receptors. (PMID:12226756)
• Full-length Mig-6, but not CRIB domain-deleted Mig-6 (DeltaMig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of kappaB (NFkappaB). (PMID:12384522)
• Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. (PMID:12387890)
• MIG-6/RALT binds to ligand-activated ErbB dimers and inhibits their signalling activity, as assessed in cell proliferation assays and biochemical analysis of activated downstream pathways such as ERK and AKT. (PMID:12833145)
• Gene 33 is a physiological feedback inhibitor of the EGFR, functioning to inhibit EGFR phosphorylation and all events induced by EGFR activation (PMID:15556944)
• C-terminal region of the Gene33 protein (ERBB receptor feedback inhibitor 1) regulates MEK-ERK pathway-directed Elk-dependent transcription. (PMID:15696545)
• Loss of MIG-6 mRNA and protein expression occurs in ERBB2-amplified breast cancer cell lines and enhances ERBB2 oncogenic signalling. (PMID:15856022)
• RALT mRNA and protein expression was strongly and selectively reduced in ERBB2-amplified breast cancer cell lines, loss of RALT signalling may adversely affect tumor responses to ErbB-2-targeting agents (PMID:15856022)
• Expression of a K14-RALT transgene in mouse skin generates a waved-like phenotype ( wavy coat, curly whiskers and open eyes at birth). Thus, excess RALT function suppresses EGFR function during skin morphogenesis. (PMID:16007071)
• MIG-6 is a tumor-suppressor gene associated with lung cancer (PMID:16819504)
• Review highlights important roles of Mig-6 in regulating stress response, maintaining homeostasis in tissues like joints or cardiac muscle, and functioning as a tumor suppressor. (PMID:17351343)
• The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity. (PMID:17599051)
• Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approximately 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain (PMID:18046415)
• new hypoxia-inducible and SOX9-regulated genes, Gdf10 and Chm-I. In addition, Mig6 and InhbA were induced by hypoxia, predominantly via HIF-2alpha (PMID:18077449)
• High mitogen inducible gene 6 expression in papillary thyroid cancer is associated with greater survival and MIG-6 expression correlates directly with EGFR expression. (PMID:19040996)
• Mig-6 is a critical regulator of the response of the endometrium to estrogen in regulating tissue homeostasis (PMID:19439667)
• cells accumulate MIG6 as an inherent negative regulator to suppress excess EGFR activity when basal EGFR kinase activity is considerably high. (PMID:19674104)
• Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma. (PMID:20044804)
• Mig-6 controls EGFR trafficking and suppresses gliomagenesis (PMID:20351267)
• MIG6 drives endocytosis and degradation of kinase-inactive EGFR (PMID:20421427)
• Mig-6 knockdown in thyroid cancer cell lines resulted in epidermal growth factor receptor phosphorylation and diminished NF-kappaB activity, whereas Mig-6 overexpression had the opposite effects. (PMID:21190978)
• Mig6 plays a role in transmitting the effect of gefitinib to the downstream part of the EGFR signaling pathway. (PMID:21333004)
• results indicate that downregulated Mig-6 in NSCLC tissues may serve as a new marker that can predict the activation of EGFR signaling pathway (PMID:21739478)
• Treatment with AZD6244 reduced the expression of mitogen-inducible gene 6 (MIG6). (PMID:22082529)
• Knockdown of PIM-1 but not of PIM-2 or PIM-3 also up regulates MIG6 expression, which identifies MIG6 as a PIM-1 regulated gene prostate cancer cells. (PMID:22193779)
• These results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. (PMID:22505024)
• MIG-6 gene is differentially regulated in lung cancer and melanoma and can be epigenetically silenced by inhibitors of methylation and histone deacetylation. (PMID:22701735)
• ERRFI1 + 808 T/G polymorphism confers protective effect on diabetic nephropathy in a Korean population. (PMID:23324575)
• Mig6 functions as a molecular brake for beta-cell proliferation during glucocorticoid treatment in beta-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional beta-cell mass. (PMID:23384834)
• The Mig-6 induces premature senescence via functioning in regulation of cellular senescence in normal diploid fibroblasts. (PMID:23746120)
• SPRY2 and MIG6 are important regulators of wild-type and mutant EGFR trafficking and points to an EGFR expression-independent function of SPRY2 in the regulation of ERK activity that may impact cellular sensitivity to EGFR inhibitors (PMID:23868981)
• Data indicate that EGFR activity, which was more accurately predicted by the ratio of mitogen-inducible gene 6 (Mig6)/EGFR, highly correlated with erlotinib sensitivity in panels of cancer cell lines of different tissue origins. (PMID:23935914)
• The EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM. (PMID:24425048)
• Mechanistic model of EGFR endocytosis to determine the relative contributions of three parallel pathways of MIG6, ubiquitin ligase CBL and Sprouty2. (PMID:24445374)
• Mig-6 is a potential biomarker for evaluation of tumor prognosis of lung cancer. (PMID:24573418)
• Mig-6 reduces pRb phosphorylation at Ser249/ Thr252 in both primary and B-Raf V600E oncogene expressing. (PMID:24815188)
• The TGFbeta-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. (PMID:24830724)
• Demonstrate that Mig-6 could reverse gefitinib resistance through inhibition of EGFR/ERK pathway in non-small cell lung cancer cell lines. (PMID:25400829)
• MIG6 is a potent tumor suppressor for mutant EGFR-driven lung tumor initiation and progression in mice and provides a possible mechanism by which mutant EGFR can partially circumvent this tumor suppressor in human lung adenocarcinoma. (PMID:25735773)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	errfi1a	ENSDARG00000104039
mus_musculus	Errfi1	ENSMUSG00000028967
rattus_norvegicus	Errfi1	ENSRNOG00000058186

Protein

Protein identifiers

ERBB receptor feedback inhibitor 1 — Q9UJM3 (reviewed: Q9UJM3)

Alternative names: Mitogen-inducible gene 6 protein

All UniProt accessions (6): Q9UJM3, I6S2Y9, K7EJB4, K7EMD2, K7ENI4, K7ENN7

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development.

Subunit / interactions. Interacts with ERBB2. Interacts with EGFR.

Subcellular location. Cytoplasm. Cell membrane. Nucleus.

Domain organisation. The EGFR-binding region prevents binding of a cyclin-like activator to the EGFR kinase domain, and thereby keeps EGFR in an inactive conformation. Also maintains EGFR in an inactive conformation by preventing formation of an asymmetric homodimer.

Induction. Levels are very low in quiescent cells. Up-regulated by mitogens.

Similarity. Belongs to the MIG6 family.

RefSeq proteins (1): NP_061821* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015116	Cdc42-bd-like	Domain
IPR052112	EGFR_SigReg_Kinase	Family

Pfam: PF09027

UniProt features (28 total): modified residue 7, compositionally biased region 5, mutagenesis site 3, region of interest 3, sequence variant 2, sequence conflict 2, strand 2, initiator methionine 1, chain 1, helix 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4ZJV	X-RAY DIFFRACTION	2.7
2RFE	X-RAY DIFFRACTION	2.9
4R3P	X-RAY DIFFRACTION	2.9
4R3R	X-RAY DIFFRACTION	3.25
4I21	X-RAY DIFFRACTION	3.37
2RF9	X-RAY DIFFRACTION	3.5
2RFD	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJM3-F1	57.20	0.10

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 (7): 2, 127, 131, 251, 273, 302, 461

Mutagenesis-validated functional residues (3):

Position	Phenotype
346	abolishes inhibition of egfr activity.
352	abolishes inhibition of egfr activity.
358	abolishes inhibition of egfr activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 545 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, HNF3ALPHA_Q6, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_CARTILAGE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY

GO Biological Process (50): liver development (GO:0001889), tissue homeostasis (GO:0001894), glucose metabolic process (GO:0006006), bile acid biosynthetic process (GO:0006699), apoptotic process (GO:0006915), epidermal growth factor receptor signaling pathway (GO:0007173), negative regulation of epidermal growth factor-activated receptor activity (GO:0007175), embryo implantation (GO:0007566), cholesterol metabolic process (GO:0008203), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), cell migration (GO:0016477), negative regulation of protein autophosphorylation (GO:0031953), response to estradiol (GO:0032355), response to progesterone (GO:0032570), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of tumor necrosis factor production (GO:0032720), cellular response to insulin stimulus (GO:0032869), negative regulation of collagen biosynthetic process (GO:0032966), uterine epithelium development (GO:0035847), chondrocyte proliferation (GO:0035988), limb joint morphogenesis (GO:0036022), cellular response to platelet-derived growth factor stimulus (GO:0036120), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), cholesterol homeostasis (GO:0042632), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), skin morphogenesis (GO:0043589), regulation of keratinocyte differentiation (GO:0045616), lung alveolus development (GO:0048286), epithelial cell proliferation (GO:0050673), progesterone receptor signaling pathway (GO:0050847), cartilage development (GO:0051216), lung vasculature development (GO:0060426), lung epithelium development (GO:0060428), fat pad development (GO:0060613), regulation of type B pancreatic cell proliferation (GO:0061469), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to epidermal growth factor stimulus (GO:0071364), cellular hyperosmotic response (GO:0071474), cellular response to dexamethasone stimulus (GO:0071549)

GO Molecular Function (6): GTPase activator activity (GO:0005096), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), small GTPase binding (GO:0031267), protein binding (GO:0005515), kinase binding (GO:0019900)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
gland development	1
hepaticobiliary system development	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
hexose metabolic process	1
bile acid metabolic process	1
monocarboxylic acid biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
ERBB signaling pathway	1
epidermal growth factor receptor activity	1
negative regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of protein tyrosine kinase activity	1
negative regulation of signaling receptor activity	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to chemical	1
macromolecule biosynthetic process	1
cell motility	1
negative regulation of protein phosphorylation	1
negative regulation of protein kinase activity	1
regulation of protein autophosphorylation	1
protein autophosphorylation	1
response to lipid	1
response to oxygen-containing compound	1
response to steroid hormone	1
response to ketone	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
response to insulin	1
cellular response to peptide hormone stimulus	1

Protein interactions and networks

STRING

881 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERRFI1	ERBB2	P04626	770
ERRFI1	EGFR	P00533	669
ERRFI1	AKT1	P31749	549
ERRFI1	EGF	P01133	525
ERRFI1	SLC45A1	Q9Y2W3	500
ERRFI1	SRC	P12931	489
ERRFI1	STAT3	P40763	480
ERRFI1	CDKN1A	P38936	463
ERRFI1	B3GNT2	Q9NY97	457
ERRFI1	ATF3	P18847	453
ERRFI1	EGR1	P18146	443
ERRFI1	BTK	Q06187	420
ERRFI1	FOSB	P53539	419
ERRFI1	SOX4	Q06945	417
ERRFI1	COMMD1	Q8N668	399

IntAct

85 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
EGFR	ERBB2	psi-mi:“MI:0914”(association)	0.950
GRB2	ERRFI1	psi-mi:“MI:0915”(physical association)	0.940
ERRFI1	EGFR	psi-mi:“MI:0407”(direct interaction)	0.930
EGFR	ERRFI1	psi-mi:“MI:0407”(direct interaction)	0.930
EGFR	ERRFI1	psi-mi:“MI:2364”(proximity)	0.930
ERRFI1	EGFR	psi-mi:“MI:0914”(association)	0.930
EGFR	HSP90AA1	psi-mi:“MI:0914”(association)	0.820
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
SHC1	AP2A1	psi-mi:“MI:0914”(association)	0.730
UBASH3B	EGFR	psi-mi:“MI:0914”(association)	0.690
ERRFI1	ERBB2	psi-mi:“MI:0915”(physical association)	0.660
SHC1	AP2A2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
FYN	ERRFI1	psi-mi:“MI:0915”(physical association)	0.560
YWHAE	SRSF10	psi-mi:“MI:0914”(association)	0.560
SFN	ERRFI1	psi-mi:“MI:0915”(physical association)	0.560
ERRFI1	SFN	psi-mi:“MI:0915”(physical association)	0.560
SFN	ERRFI1	psi-mi:“MI:0403”(colocalization)	0.560
ERRFI1	AKT1	psi-mi:“MI:0915”(physical association)	0.550
ERRFI1	AKT1	psi-mi:“MI:2364”(proximity)	0.550

BioGRID (166): ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Two-hybrid), ERRFI1 (Affinity Capture-MS), ERRFI1 (Affinity Capture-MS), YWHAE (Affinity Capture-MS), YWHAZ (Affinity Capture-MS)

ESM2 similar proteins: A0A140LFM6, A0A1B0GVH6, A0A2K1JJ00, A0JM08, A2BIL8, A2RRY8, A4IGV6, B0BK70, B3DHS1, E9Q309, F1QPR4, F1QR98, P32845, P34469, P48437, P97440, Q06616, Q06813, Q1KN21, Q1LV19, Q1RMQ5, Q3ZBS1, Q498L0, Q4JQW6, Q4R309, Q4V7B2, Q5RDK8, Q5SW79, Q5VT06, Q62417, Q62770, Q68FQ8, Q6A065, Q6DFB0, Q6PKN7, Q8K0T7, Q8N9R6, Q8VEB3, Q91018, Q92786

Diamond homologs: P05432, Q99JZ7, Q9UJM3, O54967, Q07912, Q17R13, Q5U2X5

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
SRC	“down-regulates activity”	ERRFI1	phosphorylation
ERRFI1	“down-regulates quantity by destabilization”	EGFR	binding
EGFR	“up-regulates activity”	ERRFI1	phosphorylation
ERRFI1	down-regulates	EGFR	binding
ERRFI1	“down-regulates activity”	EGFR	binding
ERRFI1	“down-regulates activity”	ERBB2	binding
CHEK1	“down-regulates activity”	ERRFI1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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	8	129.6×	9e-14
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	114.3×	2e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	114.3×	2e-13
Signaling by ERBB2 ECD mutants	6	85.8×	2e-09
Activation of BH3-only proteins	8	84.5×	2e-12
Constitutive Signaling by EGFRvIII	5	75.9×	1e-07
Signaling by ERBB2 TMD/JMD mutants	6	60.7×	2e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	60.7×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	9	45.5×	3e-10
cellular response to epidermal growth factor stimulus	6	38.9×	4e-06
protein targeting	5	37.4×	4e-05
intracellular protein localization	8	17.1×	6e-06
protein autophosphorylation	5	14.8×	1e-03
heart development	8	12.9×	4e-05
protein phosphorylation	7	9.7×	7e-04
protein stabilization	7	9.6×	7e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

536 predictions. Top by Δscore:

Variant	Effect	Δscore
1:8015493:A:AC	donor_gain	1.0000
1:8015494:C:CC	donor_gain	1.0000
1:8015700:G:GC	acceptor_gain	1.0000
1:8026152:CCTTA:C	donor_loss	1.0000
1:8026153:CTTA:C	donor_loss	1.0000
1:8026154:TTAC:T	donor_loss	1.0000
1:8026155:TA:T	donor_loss	1.0000
1:8026156:A:AC	donor_gain	1.0000
1:8026156:AC:A	donor_gain	1.0000
1:8026156:ACC:A	donor_gain	1.0000
1:8026157:C:CC	donor_gain	1.0000
1:8026157:CC:C	donor_gain	1.0000
1:8026157:CCC:C	donor_gain	1.0000
1:8014393:TGCC:T	acceptor_gain	0.9900
1:8014395:CC:C	acceptor_gain	0.9900
1:8014395:CCCTG:C	acceptor_loss	0.9900
1:8014396:CC:C	acceptor_gain	0.9900
1:8015494:CT:C	donor_gain	0.9900
1:8015506:A:AC	donor_gain	0.9900
1:8015507:C:CC	donor_gain	0.9900
1:8015689:TTCC:T	acceptor_gain	0.9900
1:8015691:CC:C	acceptor_gain	0.9900
1:8015692:CC:C	acceptor_gain	0.9900
1:8015693:C:CC	acceptor_gain	0.9900
1:8015693:CTGG:C	acceptor_loss	0.9900
1:8015694:T:C	acceptor_loss	0.9900
1:8015700:G:C	acceptor_gain	0.9900
1:8015709:A:C	acceptor_gain	0.9900
1:8015488:TACTT:T	donor_loss	0.9800
1:8015489:ACTTA:A	donor_loss	0.9800

AlphaMissense

3015 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:8013412:A:G	L396P	0.999
1:8013429:A:C	S390R	0.999
1:8013429:A:T	S390R	0.999
1:8013431:T:G	S390R	0.999
1:8013460:A:G	L380P	0.999
1:8013543:A:C	F352L	0.999
1:8013543:A:T	F352L	0.999
1:8013545:A:G	F352L	0.999
1:8013546:G:C	S351R	0.999
1:8013546:G:T	S351R	0.999
1:8013548:T:G	S351R	0.999
1:8013416:A:C	Y395D	0.998
1:8013419:A:C	Y394D	0.998
1:8013422:G:C	H393D	0.998
1:8013562:A:G	M346T	0.998
1:8013409:A:G	L397P	0.997
1:8013420:A:C	H393Q	0.997
1:8013420:A:T	H393Q	0.997
1:8013544:A:G	F352S	0.997
1:8013561:C:A	M346I	0.997
1:8013561:C:G	M346I	0.997
1:8013561:C:T	M346I	0.997
1:8013454:A:T	I382N	0.996
1:8013463:A:C	I379S	0.996
1:8013463:A:G	I379T	0.996
1:8013463:A:T	I379N	0.996
1:8013541:G:T	A353D	0.996
1:8013544:A:C	F352C	0.996
1:8013633:T:A	R322S	0.996
1:8013633:T:G	R322S	0.996

dbSNP variants (sampled 300 via entrez): RS1000225129 (1:8020539 C>A), RS1000961307 (1:8018412 C>A,T), RS1000967600 (1:8025216 G>A,C), RS1001113616 (1:8020184 G>A,C), RS1001226749 (1:8021966 T>G), RS1001309787 (1:8014581 G>A), RS1001802010 (1:8021752 T>C), RS1001803313 (1:8014756 G>A), RS1001937574 (1:8015907 A>G), RS1002031534 (1:8026228 G>A,C), RS1002135887 (1:8020084 A>C,G), RS1002603653 (1:8019830 A>C), RS1003530553 (1:8023236 G>A,C,T), RS1003594715 (1:8015427 T>C), RS1003612276 (1:8017855 T>C)

Disease associations

OMIM: gene MIM:608069 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002286_5	Ischemic stroke	6.000000e-08
GCST003813_4	Response to antidepressants and depression	2.000000e-06
GCST004131_79	Inflammatory bowel disease	1.000000e-12
GCST004132_92	Crohn’s disease	3.000000e-06
GCST004133_62	Ulcerative colitis	4.000000e-09
GCST005007_9	Strep throat	4.000000e-08
GCST005191_1	Hair shape	9.000000e-14
GCST007565_140	Morning person	6.000000e-26
GCST011743_10	HDL cholesterol levels in HIV infection	6.000000e-06
GCST012226_403	Waist circumference adjusted for body mass index	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ERRFI1 E384*	Erlotinib	Cholangiocarcinoma	Sensitivity/Response	CIViC C	EID1724

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases methylation, increases expression, increases phosphorylation, decreases expression	5
Estradiol	affects cotreatment, decreases expression, increases expression	5
trichostatin A	increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
chloropicrin	affects expression, decreases expression	2
Decitabine	decreases reaction, increases methylation, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Progesterone	increases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects expression, increases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
bisphenol A	decreases expression	1
lead acetate	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	increases expression	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
afimoxifene	increases expression, affects reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
sodium chromate(VI)	increases expression, decreases expression, decreases reaction	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
vanadyl sulfate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1W8	Abcam A-549 ERRFI1 KO	Cancer cell line	Male
CVCL_D2AL	Abcam HCT 116 ERRFI1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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