ERBB4

Summary

ERBB4 (erb-b2 receptor tyrosine kinase 4, HGNC:3432) is a protein-coding gene on chromosome 2q34, encoding Receptor tyrosine-protein kinase erbB-4 (Q15303). Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and a…. In precision oncology, ERBB4 Mutation confers sensitivity to Lapatinib in Melanoma (CIViC Level D); 3 further curated variant–drug associations are listed below.

This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.

Source: NCBI Gene 2066 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 19 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 66 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 792 total — 3 pathogenic, 9 likely-pathogenic (top 4% of genes corpus-wide)
• GTEx eGene: eQTL in 16 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 53
• Drug target: yes — 7 curated mechanism-of-action drugs, 4 via a complex or family; 47 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 3 — Afatinib Dimaleate, Dacomitinib, Neratinib
• Approved drugs acting on a complex or family including it: 1 — Vandetanib (Epidermal growth factor receptor)
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 10 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.36 (moderately constrained)
• MANE Select transcript: NM_005235
• Interaction hub: 2,839 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3432
Approved symbol	ERBB4
Name	erb-b2 receptor tyrosine kinase 4
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	ALS19, HER4
Ensembl gene	ENSG00000178568
Ensembl biotype	protein_coding
OMIM	600543
Entrez	2066

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000342788

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 3: 3, TSL 5: 2

ENST00000342788, ENST00000260943, ENST00000435846, ENST00000436443, ENST00000459774, ENST00000463121, ENST00000484474, ENST00000484594, ENST00001144709

RefSeq mRNA: 4 — MANE Select: NM_005235 NM_001042599, NM_001439005, NM_001439006, NM_005235

CCDS: CCDS2394, CCDS42811

Canonical transcript exons

ENST00000342788 — 28 exons

Exon	Start	End
ENSE00000965161	211428408	211428483
ENSE00000965162	211424155	211424301
ENSE00001002878	211420441	211420611
ENSE00001002880	211430945	211431100
ENSE00001002882	211422007	211422104
ENSE00001295501	211561903	211562088
ENSE00001302849	211386853	211387150
ENSE00001329579	211387945	211387992
ENSE00001563494	211375717	211384060
ENSE00003466941	211619177	211619275
ENSE00003471607	211673164	211673257
ENSE00003486501	211701967	211702166
ENSE00003501799	211712050	211712176
ENSE00003512307	211704104	211704194
ENSE00003512540	211750639	211750704
ENSE00003542689	211623922	211624044
ENSE00003543170	211713535	211713648
ENSE00003570459	211947430	211947616
ENSE00003595381	211630462	211630594
ENSE00003600790	212124752	212124903
ENSE00003610472	211679052	211679184
ENSE00003612141	211657754	211657828
ENSE00003620037	211788025	211788159
ENSE00003630686	211725076	211725194
ENSE00003662423	211705318	211705391
ENSE00003676702	211665323	211665477
ENSE00003681368	211722393	211722534
ENSE00003843480	212538449	212538802

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 99.06.

FANTOM5 (CAGE): breadth broad, TPM avg 7.3550 / max 325.6449, expressed in 604 samples.

Highest expression (Bgee): endothelial cell, secondary oocyte, cranial nerve II, middle temporal gyrus, oocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ERBB4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 16 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.5e-27	+0.34	2:212538240:A:AC
Artery Aorta	sqtl	3.0e-18	+0.85	2:211700633:C:T
Pancreas	eqtl	1.0e-11	+1.12	2:212284064:G:A
Brain Cerebellar Hemisphere	eqtl	4.9e-09	-0.48	2:212304789:T:C
Muscle Skeletal	eqtl	8.4e-08	-0.32	2:212541228:G:A
Skin Sun Exposed Lower leg	eqtl	1.8e-07	+0.19	2:212242123:T:A
Pituitary	eqtl	6.7e-07	-0.27	2:212537981:A:G
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-06	+0.22	2:212541734:C:CA
Artery Aorta	eqtl	3.5e-06	-0.19	2:212346250:G:C
Brain Cerebellum	eqtl	6.7e-06	+0.42	2:211784387:T:C
Stomach	eqtl	1.7e-05	+0.19	2:212379614:A:T
Artery Coronary	sqtl	4.2e-05	-0.64	2:211700633:C:T
Thyroid	eqtl	1.6e-04	-0.15	2:212376522:T:C
Adipose Subcutaneous	eqtl	1.8e-04	-0.27	2:212357722:T:C
Adipose Visceral Omentum	eqtl	3.5e-04	-0.24	2:212372941:A:T
Colon Sigmoid	eqtl	5.1e-04	-0.35	2:212299670:T:C
Colon Transverse	eqtl	4.0e-03	-0.24	2:211683210:A:G
Brain Caudate basal ganglia	sqtl	1.6e-02	-0.57	2:211701531:C:T
Testis	eqtl	4.9e-02	+0.21	2:212652202:A:G

FANTOM5 promoters

showing 10 of 14 alternative TSS:

Promoter ID	TPM avg	Samples expressed
33507	3.0193	489
33503	1.1758	350
33506	1.1064	280
33508	0.7827	284
33509	0.4210	186
33505	0.2007	103
33487	0.1769	102
33502	0.1663	95
33499	0.0792	48
33504	0.0638	30

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.06	gold quality
secondary oocyte	CL:0000655	97.75	gold quality
cranial nerve II	UBERON:0000941	94.75	gold quality
middle temporal gyrus	UBERON:0002771	94.55	gold quality
oocyte	CL:0000023	94.54	gold quality
buccal mucosa cell	CL:0002336	94.32	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.07	gold quality
entorhinal cortex	UBERON:0002728	91.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.35	gold quality
orbitofrontal cortex	UBERON:0004167	90.98	gold quality
right uterine tube	UBERON:0001302	90.78	gold quality
corpus callosum	UBERON:0002336	90.14	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.62	gold quality
postcentral gyrus	UBERON:0002581	89.62	gold quality
CA1 field of hippocampus	UBERON:0003881	89.23	gold quality
metanephric glomerulus	UBERON:0004736	89.22	gold quality
parietal lobe	UBERON:0001872	89.15	gold quality
renal glomerulus	UBERON:0000074	89.02	gold quality
superior frontal gyrus	UBERON:0002661	89.00	gold quality
substantia nigra pars compacta	UBERON:0001965	88.85	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.26	gold quality
renal medulla	UBERON:0000362	88.08	gold quality
globus pallidus	UBERON:0001875	87.65	gold quality
medial globus pallidus	UBERON:0002477	87.55	gold quality
primary visual cortex	UBERON:0002436	87.23	gold quality
occipital lobe	UBERON:0002021	87.11	gold quality
kidney epithelium	UBERON:0004819	87.11	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.09	gold quality
lateral globus pallidus	UBERON:0002476	86.80	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.37	gold quality
cerebellar vermis	UBERON:0004720	86.35	gold quality
ventral tegmental area	UBERON:0002691	85.12	gold quality
parotid gland	UBERON:0001831	84.99	gold quality
nephron tubule	UBERON:0001231	84.59	gold quality
temporal lobe	UBERON:0001871	84.12	gold quality
frontal pole	UBERON:0002795	84.07	gold quality
superior vestibular nucleus	UBERON:0007227	83.99	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.62	gold quality
middle frontal gyrus	UBERON:0002702	83.04	gold quality
medulla oblongata	UBERON:0001896	81.77	gold quality
inferior olivary complex	UBERON:0002127	81.13	gold quality
epithelium of mammary gland	UBERON:0003244	81.06	gold quality
prefrontal cortex	UBERON:0000451	80.96	gold quality
germinal epithelium of ovary	UBERON:0001304	80.85	gold quality
frontal cortex	UBERON:0001870	80.73	gold quality
cerebral cortex	UBERON:0000956	80.70	gold quality
telencephalon	UBERON:0001893	80.69	gold quality
neocortex	UBERON:0001950	80.47	gold quality
blood vessel layer	UBERON:0004797	80.38	gold quality
midbrain	UBERON:0001891	80.31	gold quality
bronchial epithelial cell	CL:0002328	80.22	gold quality
pons	UBERON:0000988	80.20	gold quality
substantia nigra	UBERON:0002038	80.03	gold quality
caudate nucleus	UBERON:0001873	79.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.98	gold quality
mammary duct	UBERON:0001765	79.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.31	gold quality
putamen	UBERON:0001874	79.22	gold quality
amygdala	UBERON:0001876	79.20	gold quality
Ammon’s horn	UBERON:0001954	79.16	gold quality
forebrain	UBERON:0001890	79.12	gold quality
left ventricle myocardium	UBERON:0006566	79.10	silver quality
pigmented layer of retina	UBERON:0001782	79.09	gold quality
cingulate cortex	UBERON:0003027	79.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.01	gold quality
anterior cingulate cortex	UBERON:0009835	78.90	gold quality
brain	UBERON:0000955	78.72	gold quality
inferior vagus X ganglion	UBERON:0005363	78.50	gold quality
kidney	UBERON:0002113	78.46	gold quality
central nervous system	UBERON:0001017	78.42	gold quality
metanephros	UBERON:0000081	78.20	gold quality
nucleus accumbens	UBERON:0001882	78.13	gold quality
ascending aorta	UBERON:0001496	77.43	gold quality
thoracic aorta	UBERON:0001515	77.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	77.00	gold quality
epithelium of bronchus	UBERON:0002031	76.99	gold quality
ganglionic eminence	UBERON:0004023	76.88	gold quality
subthalamic nucleus	UBERON:0001906	76.57	gold quality
bronchus	UBERON:0002185	76.44	gold quality
hypothalamus	UBERON:0001898	76.40	gold quality
paraflocculus	UBERON:0005351	75.92	gold quality
myocardium	UBERON:0002349	75.86	gold quality
tibialis anterior	UBERON:0001385	75.44	silver quality
adult mammalian kidney	UBERON:0000082	75.36	gold quality
descending thoracic aorta	UBERON:0002345	75.17	gold quality
mammary gland	UBERON:0001911	75.16	gold quality
thoracic mammary gland	UBERON:0005200	75.11	gold quality
cortical plate	UBERON:0005343	74.49	gold quality
cerebellum	UBERON:0002037	73.82	gold quality
right frontal lobe	UBERON:0002810	73.42	gold quality
biceps brachii	UBERON:0001507	73.41	silver quality
deltoid	UBERON:0001476	73.40	silver quality
endometrium epithelium	UBERON:0004811	73.39	gold quality
aorta	UBERON:0000947	72.96	gold quality
dorsal plus ventral thalamus	UBERON:0001897	72.87	gold quality
fallopian tube	UBERON:0003889	72.87	gold quality
cerebellar cortex	UBERON:0002129	72.62	gold quality
cortex of kidney	UBERON:0001225	72.54	gold quality
choroid plexus epithelium	UBERON:0003911	72.51	gold quality
cardiac atrium	UBERON:0002081	72.46	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	12646.74
E-GEOD-131882	yes	11932.00
E-CURD-119	yes	11857.97
E-HCAD-30	yes	8231.65
E-GEOD-180759	yes	7087.96
E-HCAD-25	yes	6259.30
E-GEOD-109979	yes	2032.22
E-GEOD-93593	yes	1085.94
E-MTAB-7316	yes	725.89
E-GEOD-111727	yes	161.79
E-HCAD-10	yes	29.46
E-MTAB-5061	yes	9.54
E-ANND-3	yes	8.21
E-GEOD-81608	yes	5.84
E-ENAD-27	yes	5.28

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	50.9
Nucleus accumbens	tissue	49.3
Postcentral gyrus	tissue	42.4
Cerebellum	tissue	42.0	low
Amygdala	tissue	41.3
Substantia nigra	tissue	40.2
Periaqueductal gray	tissue	39.5
Hippocampal formation	tissue	39.0
Hypothalamus	tissue	38.9
Ventral forebrain	tissue	37.5
Olfactory bulb	tissue	37.5
Hippocampus	tissue	37.1	low
Septum	tissue	37.0
Cerebral cortex	tissue	36.9	not detected
Motor cortex	tissue	36.9
Entorhinal cortex	tissue	36.4
Retrosplenial cortex	tissue	36.2
Retrosplenial and cingulate cortex	tissue	35.5
Midbrain	tissue	35.4
Insular cortex	tissue	35.1
Somatosensory cortex	tissue	34.6
Prefrontal cortex	tissue	33.9
Occipital cortex	tissue	33.6
Pons	tissue	32.7
Temporal cortex	tissue	31.9
Putamen	tissue	30.8
Thalamus	tissue	30.4
Locus coeruleus	tissue	30.4
Medulla oblongata	tissue	30.1
Basal ganglia	tissue	28.7	low
Superior colliculi	tissue	27.2
Spinal cord	tissue	22.5
Frontal cortex	tissue	13.6
Choroid plexus	tissue	12.3
Caudate putamen	tissue	12.0
Fallopian tube	tissue	10.6	low
Breast	tissue	5.2	medium
Kidney	tissue	4.8	low
Salivary gland	tissue	4.4	low
Testis	tissue	3.0	medium
Parathyroid gland	tissue	2.9	medium
Cervix	tissue	2.8	medium
Heart muscle	tissue	2.6	not detected
Pituitary gland	tissue	2.2
Retina	tissue	1.8
Skeletal muscle	tissue	1.4	not detected
Tongue	tissue	1.4
Thyroid gland	tissue	1.4	low
Seminal vesicle	tissue	1.1	medium
Lung	tissue	0.8	medium
Pancreas	tissue	0.5	low
Skin 1	tissue	0.3	medium
Adrenal gland	tissue	0.3
Stomach 1	tissue	0.2	medium
Adipose tissue	tissue	0.2	medium
Prostate	tissue	0.2	medium
Ovary	tissue	0.1	low
Vagina	tissue	0.1	medium
Esophagus	tissue	0.1	low
Urinary bladder	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Median raphe nucleus (60.1), Dorsal raphe nucleus (54.4), Ventral tegmental area (54.1), Caudate nucleus (53.5), Nucleus of the diagonal band (52.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ADAM10, AP1, DLX1, ESR1, WWP1

miRNA regulators (miRDB)

Targeting ERBB4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 346 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6891-5P	99.98	66.53	1372

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.357, missense Z 2.83 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000342788 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:211,383,618–211,383,885	84 / 110.8	0.76	no
2:211,383,886–211,420,499	252 / 241.3	1.04	no
2:211,420,500–211,630,532	314 / 437.6	0.72	no
2:211,630,533–211,702,030	245 / 247.5	0.99	no
2:211,702,031–212,538,530	438 / 586.9	0.75	no
ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• cleavage by gamma-secretase releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus (PMID:11679632)
• ErbB4 expression was observed through all stages of chondrocytic differentiation in vitro. (PMID:12297288)
• deletion of the PDZ domain recognition motif does abrogate the gamma-secretase cleavage of ErbB-4 (PMID:12454007)
• ErbB4 is specifically associated with neuritic plaques in the hippocampus of Alzheimer disease patients. (PMID:12528817)
• ErbB4 signaling is growth inhibitory and may be coupled to tumor suppression in prostate cells (PMID:12637154)
• Expression of HER4 protein correlates with favourable tumor stage in pancreatic cancer patients. (PMID:12678544)
• YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription (PMID:12807903)
• ErbB-4 characterization of the cleavage site and m80 fragment (PMID:12869563)
• Nuclear localization of the activated p80 fragment of Her-4 is associated with osteosarcoma pathogenesis (PMID:15026342)
• HER4 is involved in a non-proliferative or even protective role in breast cancer. (PMID:15084248)
• betacellulin may play a role as a local growth factor in promoting the differentiated villous trophoblastic function via ErbB-1 in early placentas and in contributing to placental growth through EVT cell function via ErbB-4 in term placentas. (PMID:15248827)
• nuclear localization of STAT5A and stimulation of the beta-casein promoter requires nuclear translocation of the ERBB4 intracellular domain 4ICD; binding of the two proteins at transcription factor target promoters results in activation of gene expression (PMID:15534001)
• ErbB4 is increased by cAMP, a potent inducer of decidualization of the endometrial stroma. (PMID:15562026)
• erbB receptor inactivation by unknown mechanisms results in altered splicing of bcl-x towards enhanced formation of proapoptotic Bcl-xS, thereby contributing to enhanced apoptotic susceptibility of failing human myocardium (PMID:15685397)
• Association of ErbB4 expression with clinical outcome is dependent on the subcellular localization of ErbB4 and that a proteinase-cleavable ErbB4 isoform promotes growth of ER-positive breast cancer and enhances ER-mediated gene transcription. (PMID:15735025)
• proteolytic processing of ERBB4 is a critical event regulating multiple receptor signaling activities (PMID:15746097)
• Absence of HER4 expression is associated with recurrence of ductal carcinoma in situ of the breast (PMID:15788662)
• HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling (PMID:15979989)
• Data show that expression of the ErbB-4 ICD fragment leads to its constitutive association with and tyrosine phosphorylation of Mdm2. (PMID:15985438)
• WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity. (PMID:16061658)
• the s80 domain of ErbB-4 may function to phosphorylate substrates in the cytoplasm or nucleus (PMID:16170367)
• Data suggested that alterations of ERBB4-mediated signaling pathway by ERBB4 mutations may contribute to the development of human cancers. (PMID:16187281)
• Results report the 2.4 A crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. (PMID:16203964)
• Mutation screening of erbB4 in 14 schizophrenics revealed 15 SNPs. (PMID:16249994)
• novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor (PMID:16251361)
• Results showed a highly significant difference between patient and control groups in three SNPs from one linkage disequilibrium block both in allele and genotype frequencies, as well as a risk haplotype. (PMID:16402353)
• Activation of Rac by heregulin beta1 is mediated not only by ErbB3 and ErbB2 but also by transactivation of EGFR, and it is independent of ErbB4. (PMID:16428439)
• A monoclonal antibody to ErbB-4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB-4. (PMID:16463386)
• ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells. (PMID:16477370)
• These experiments demonstrate a novel mechanism controlling ErbB receptor activation. Ras induces ErbB4 receptor phosphorylation in a non-autocrine manner and this activation depends on multiple Ras effector pathways and on ErbB4 kinase activity. (PMID:16518842)
• Function of HER4 and its fragments is particularly important, with \the different functions of nuclear and mitochondrial HER4 in breast cancer. (PMID:16606438)
• HER3 and HER4 has been related to a favourable prognosis in bladder cancer. (PMID:16685269)
• ErbB4 has 5 docking sites for Grb2. It is a direct binding partner for STAT5. It functions as control center & integration site for signaling processes, involving stimulation with neuregulin. (PMID:16729043)
• Neurogulin 1 induced activation of erbB4 in the prefrontal cortex in schizophrenia. (PMID:16767099)
• Cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. (PMID:16778220)
• -16 E5 protein can form a complex with ErbB4 via binding to the extracellular and transmembrane domains of ErbB4 (JM-b/CYT-1) (PMID:16819515)
• Down regulation of ERBB4 is associated with brease, prostate and ovarian cancer (PMID:16832345)
• Expression of c-erbB-4 in brain medulloblastoma and its correlation with prognosis. (PMID:16842254)
• low-level hedgehog signalling in human medulloblastoma is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects (PMID:16878160)
• Contribution of an autocrine ERBB4/estrogen receptor signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer. (PMID:16912174)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	erbb4b	ENSDARG00000089536
mus_musculus	Erbb4	ENSMUSG00000062209
rattus_norvegicus	Erbb4	ENSRNOG00000014248

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715), RET (ENSG00000165731), AXL (ENSG00000167601), ROR2 (ENSG00000169071), ALK (ENSG00000171094), INSR (ENSG00000171105), CSF1R (ENSG00000182578), EPHB3 (ENSG00000182580), EPHA10 (ENSG00000183317), ROR1 (ENSG00000185483), EPHB4 (ENSG00000196411), NTRK1 (ENSG00000198400), DDR1 (ENSG00000204580)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:104771) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 40 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal blood flow velocity	1
enlarged heart	1
abnormal myocardial fiber morphology	1
thin ventricular wall	1
absent trabeculae carneae	1
decreased atrioventricular cushion size	1
abnormal mammary gland development	1
abnormal motor neuron innervation pattern	1
abnormal sensory neuron innervation pattern	1
abnormal cranial nerve morphology	1
abnormal trigeminal nerve morphology	1
abnormal facial nerve morphology	1
abnormal vestibulocochlear nerve morphology	1
abnormal glossopharyngeal nerve morphology	1
abnormal cranial ganglia morphology	1
abnormal geniculate ganglion morphology	1
abnormal trigeminal ganglion morphology	1
hyperactivity	1
cardiac hypertrophy	1
abnormal lactation	1
premature death	1
dilated heart left ventricle	1
dilated heart right ventricle	1
dilated cardiomyopathy	1
enhanced long-term potentiation	1

+15 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Felis catus	A0M8S8	100.0%	Diamond
Gallus gallus	P13387	100.0%	Diamond
Neofelis nebulosa	Q07E37	100.0%	Diamond
Pan troglodytes	Q2QLF1	99.8%	Diamond
Gorilla gorilla gorilla	Q2IBF2	99.7%	Diamond
Pongo abelii	Q5RB23	99.7%	Diamond
Papio anubis	A0M8R7	99.3%	Diamond
Macaca mulatta	P55245	99.3%	Diamond
Colobus guereza	Q07DZ1	99.3%	Diamond
Chlorocebus aethiops	Q2IBA6	99.3%	Diamond
Aotus nancymaae	Q07DV8	99.1%	Diamond
Nomascus leucogenys	Q07DY1	99.1%	Diamond
Ateles geoffroyi	Q09YL1	99.1%	Diamond
Saimiri boliviensis boliviensis	Q09YH7	99.0%	Diamond
Plecturocebus moloch	Q2QLC0	98.6%	Diamond
Macaca fascicularis	Q1KL86	98.0%	Diamond
Callithrix jacchus	Q2QLG5	97.7%	Diamond
Ovis aries	Q09YI9	97.5%	Diamond
Bos taurus	Q769I5	97.5%	Diamond
Muntiacus muntjak	Q09YK0	97.4%	Diamond
Eulemur macaco macaco	Q2IBG7	97.4%	Diamond
Microcebus murinus	Q2QL89	97.4%	Diamond
Mustela putorius furo	Q07E24	96.4%	Diamond
Canis lupus familiaris	Q75ZY9	96.4%	Diamond
Sus scrofa	O19064	95.3%	Diamond
Equus caballus	Q2QLA9	94.9%	Diamond
Otolemur garnettii	Q2QLH6	94.0%	Diamond
Atelerix albiventris	Q00PJ8	92.0%	Diamond
Loxodonta africana	Q108U6	91.8%	Diamond
Dasypus novemcinctus	Q07E48	91.4%	Diamond
Oryctolagus cuniculus	Q09YN5	91.2%	Diamond
Mesocricetus auratus	Q60553	90.3%	Diamond
Rhinolophus ferrumequinum	Q2IBC0	90.1%	Diamond
Xenopus laevis	Q91738	88.5%	Diamond
Echinops telfairi	A1X150	87.8%	Diamond
Cyprinus carpio	Q09178	86.8%	Diamond
Ornithorhynchus anatinus	Q07E01	79.2%	Diamond
Xiphophorus maculatus	P13388	61.6%	Diamond
Drosophila melanogaster	Q9VZI2	55.7%	Diamond
Apis mellifera	P0CY46	51.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01878	ncRNA	102725079
CPS1	protein-coding	1373
CPS1-IT1	ncRNA	29034
MIR548F2	ncRNA	100313771
MIR4776-1	ncRNA	100616267
MIR4776-2	ncRNA	100616472

Protein

Protein identifiers

Receptor tyrosine-protein kinase erbB-4 — Q15303 (reviewed: Q15303)

Alternative names: Proto-oncogene-like protein c-ErbB-4, Tyrosine kinase-type cell surface receptor HER4, p180erbB4

All UniProt accessions (3): E9PDR1, Q15303, H3BLT0

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.

Subunit / interactions. Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3. Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRNPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 and SRRT. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.

Subcellular location. Cell membrane Nucleus. Mitochondrion.

Tissue specificity. Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.

Post-translational modifications. Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase. Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligands trigger phosphorylation at specific tyrosine residues, thereby creating binding sites for scaffold proteins and effectors. Constitutively phosphorylated at a basal level when overexpressed in heterologous systems; ligand binding leads to increased phosphorylation. Phosphorylation at Tyr-1035 is important for interaction with STAT1. Phosphorylation at Tyr-1056 is important for interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues. Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4.

Disease relevance. Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+). Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.

Miscellaneous. Proteolytical processing generates E4ICD1 (s80Cyt1). Proteolytical processing generates E4ICD2 (s80Cyt2).

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q15303-1	JM-A CYT-1	yes
Q15303-2	JM-B CYT-1
Q15303-3	JM-A CYT-2
Q15303-4	JM-B CYT-2

RefSeq proteins (4): NP_001036064, NP_001425934, NP_001425935, NP_005226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000494	Rcpt_L-dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR006211	Furin-like_Cys-rich_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR008266	Tyr_kinase_AS	Active_site
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016245	Tyr_kinase_EGF/ERB/XmrK_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR032778	GF_recep_IV	Domain
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR049328	TM_ErbB1	Domain
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF14843, PF21314

Enzyme classification (BRENDA)

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (203 total): strand 61, helix 41, mutagenesis site 26, disulfide bond 23, glycosylation site 11, modified residue 10, turn 7, short sequence motif 5, binding site 4, sequence variant 4, chain 2, topological domain 2, splice variant 2, signal peptide 1, active site 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDB	Title	Method	Resolution (Å)
2AHX	Crystal structure of ErbB4/HER4 extracellular domain	X-RAY DIFFRACTION	2.4
2R4B	ErbB4 kinase domain complexed with a thienopyrimidine inhibitor	X-RAY DIFFRACTION	2.4
3BCE	Crystal structure of the ErbB4 kinase	X-RAY DIFFRACTION	2.5
3U2P	Crystal structure of N-terminal three extracellular domains of ErbB4/Her4	X-RAY DIFFRACTION	2.57
3BBT	crystal structure of the ErbB4 kinase in complex with lapatinib	X-RAY DIFFRACTION	2.8
3U7U	Crystal structure of extracellular region of human epidermal growth factor receptor 4 in …	X-RAY DIFFRACTION	3.03
8U4L	Structure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain	ELECTRON MICROSCOPY	3.31
8U4I	Structure of the HER4/NRG1b Homodimer Extracellular Domain	ELECTRON MICROSCOPY	3.38
3U9U	Crystal Structure of Extracellular Domain of Human ErbB4/Her4 in complex with the Fab …	X-RAY DIFFRACTION	3.42
8U4J	Structure of the HER4/BTC Homodimer Extracellular Domain	ELECTRON MICROSCOPY	3.7
3BBW	crystal structure of the ErbB4 kinase in its inactive conformation	X-RAY DIFFRACTION	4
8U4K	Structure of the HER2/HER4/BTC Heterodimer Extracellular Domain	ELECTRON MICROSCOPY	4.27
2L2T	Solution NMR structure of the ErbB4 dimeric membrane domain	SOLUTION NMR
2LCX	Spatial Structure of the ErbB4 dimeric TM domain	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15303-F1	73.17	0.45

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 3U9U

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
843	proton acceptor

Ligand- & substrate-binding residues (4)

Position	Role
724–732	ATP
751	ATP
797–799	ATP
843–848	ATP

Post-translational modifications (10)

Type	Positions
Phosphotyrosine	875, 1035, 1056, 1150, 1162, 1188, 1202, 1242, 1258, 1284

Disulfide bonds (23)

Type	Positions
Disulfide bond	29–56, 156–186, 189–197, 193–205, 213–221, 217–229, 230–238, 234–246, 249–258, 262–289, 293–304, 308–323, 326–330, 503–512, 507–520, 523–532, 536–552, 555–569, 559–577, 580–589, 593–614, 617–625, 621–633

Glycosylation sites (11)

Type	Positions
N-linked (glcnac…) asparagine	138, 174, 181, 253, 358, 410, 473, 495, 548, 576, 620

Mutagenesis-validated functional residues (26)

Position	Phenotype
646	constitutively activated kinase.
675	abolishes proteolytic processing and nuclear localization.
681–684	abolishes nuclear localization of the erbb4 intracellular domain.
710	strongly reduced autophosphorylation.
721	no effect on kinase activity.
751	abolishes kinase activity. abolishes phosphorylation, proteolytic processing and nuclear localization.
766	strongly reduced autophosphorylation.
773	no effect on kinase activity.
782	no effect on kinase activity.
810	no effect on kinase activity.
843	loss of kinase activity.
854	no effect on kinase activity.
861	loss of kinase activity.
864	strongly reduced autophosphorylation.
872	no effect on kinase activity.
926	no effect on kinase activity.
947	constitutively autophosphorylated.
992	abolishes apc/c-mediated degradation; when associated with a-995 and a-1000.
995	abolishes apc/c-mediated degradation; when associated with a-992 and a-1000.
1000	abolishes apc/c-mediated degradation; when associated with a-992 and a-995.
1035	no effect on interaction with wwox. abolishes interaction with wwox; when associated with a-1301.
1056	abolishes interaction with nedd4 and impairs ubiquitination. promotes nuclear translocation of erbb4 intracellular domain e4icd1.
1056	abolishes interaction with wwp1; when associated with f-1301.
1301	abolishes interaction with nedd4 and impairs ubiquitination.
1301	no effect on interaction with wwox. abolishes interaction with wwox; when associated with a-1035. loss of interaction with yap1 and …

Function

Pathways and Gene Ontology

Reactome pathways

16 curated (TAS) of 20; 3 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

20 pathways:

ID	Pathway	Evidence
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer ⚕	curated
R-HSA-9664565	Signaling by ERBB2 KD Mutants ⚕	curated
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants ⚕	curated
R-HSA-8863795	Downregulation of ERBB2 signaling	curated
R-HSA-1253288	Downregulation of ERBB4 signaling	curated
R-HSA-8847993	ERBB2 Activates PTK6 Signaling	curated
R-HSA-6785631	ERBB2 Regulates Cell Motility	curated
R-HSA-9018519	Estrogen-dependent gene expression	curated
R-HSA-1963640	GRB2 events in ERBB2 signaling	curated
R-HSA-1963642	PI3K events in ERBB2 signaling	curated
R-HSA-1250342	PI3K events in ERBB4 signaling	curated
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	curated
R-HSA-1257604	PIP3 activates AKT signaling	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-1250347	SHC1 events in ERBB4 signaling	curated
R-HSA-1227986	Signaling by ERBB2	curated
R-HSA-9620244	Long-term potentiation	electronic
R-HSA-1251985	Nuclear signaling by ERBB4	electronic
R-HSA-1250196	SHC1 events in ERBB2 signaling	electronic
R-HSA-1236394	Signaling by ERBB4	electronic

MSigDB gene sets: 545 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_PHOSPHORYLATION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_SYNAPSE_ASSEMBLY, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, CMYB_01, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP

GO Biological Process (43): neural crest cell migration (GO:0001755), positive regulation of protein phosphorylation (GO:0001934), DNA-templated transcription (GO:0006351), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), epidermal growth factor receptor signaling pathway (GO:0007173), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), nervous system development (GO:0007399), synapse assembly (GO:0007416), heart development (GO:0007507), lactation (GO:0007595), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), embryonic pattern specification (GO:0009880), cell migration (GO:0016477), peptidyl-tyrosine phosphorylation (GO:0018108), central nervous system morphogenesis (GO:0021551), olfactory bulb interneuron differentiation (GO:0021889), neuron differentiation (GO:0030182), regulation of cell migration (GO:0030334), ERBB4 signaling pathway (GO:0038130), ERBB2-ERBB4 signaling pathway (GO:0038135), ERBB4-ERBB4 signaling pathway (GO:0038138), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), mitochondrial fragmentation involved in apoptotic process (GO:0043653), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), protein autophosphorylation (GO:0046777), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of cardiac muscle cell proliferation (GO:0060045), mammary gland epithelial cell differentiation (GO:0060644), mammary gland alveolus development (GO:0060749), cardiac muscle tissue regeneration (GO:0061026), positive regulation of ERK1 and ERK2 cascade (GO:0070374), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), cell surface receptor signaling pathway (GO:0007166), positive regulation of biosynthetic process (GO:0009891), mammary gland development (GO:0030879), positive regulation of phosphate metabolic process (GO:0045937)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), epidermal growth factor receptor activity (GO:0005006), epidermal growth factor receptor binding (GO:0005154), ATP binding (GO:0005524), neuregulin receptor activity (GO:0038131), protein homodimerization activity (GO:0042803), GABA receptor binding (GO:0050811), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (18): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), basolateral plasma membrane (GO:0016323), neuromuscular junction (GO:0031594), presynaptic membrane (GO:0042734), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), membrane (GO:0016020), organelle (GO:0043226)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Signaling by ERBB2	6
Signaling by ERBB4	4
Signaling by Receptor Tyrosine Kinases	2
Signaling by ERBB2 in Cancer	2
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1
ESR-mediated signaling	1
Post NMDA receptor activation events	1

GO top-level categories

showing 60 of 85 GO namespaces:

Category	Terms
cellular anatomical structure	5
synapse	3
protein phosphorylation	2
cell population proliferation	2
regulation of cell population proliferation	2
intracellular membrane-bounded organelle	2
cytoplasm	2
plasma membrane region	2
synaptic membrane	2
neural crest cell development	1
mesenchymal cell migration	1
regulation of protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
gene expression	1
RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
ERBB signaling pathway	1
cell surface receptor signaling pathway via STAT	1
system development	1
animal gross anatomical part developmental process	1
nervous system development	1
cell junction assembly	1
synapse organization	1
animal organ development	1
circulatory system development	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
positive regulation of cellular process	1
negative regulation of cellular process	1
pattern specification process	1
embryo development	1
cell motility	1
central nervous system development	1
anatomical structure morphogenesis	1
olfactory bulb development	1
central nervous system neuron differentiation	1
cell differentiation	1
generation of neurons	1
cell migration	1
regulation of cell motility	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
transmembrane receptor protein tyrosine kinase activity	1
epidermal growth factor receptor signaling pathway	1
epidermal growth factor binding	1
growth factor receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transmembrane signaling receptor activity	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 75 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
ERBB4 signaling pathway	BP	direct assay
ERBB4-ERBB4 signaling pathway	BP	direct assay
cell migration	BP	direct assay
cell surface receptor protein tyrosine kinase signaling pathway	BP	direct assay
lactation	BP	mutant phenotype
mitochondrial fragmentation involved in apoptotic process	BP	mutant phenotype
negative regulation of apoptotic process	BP	mutant phenotype
negative regulation of cell population proliferation	BP	mutant phenotype
peptidyl-tyrosine phosphorylation	BP	direct assay
positive regulation of DNA-templated transcription	BP	mutant phenotype
positive regulation of ERK1 and ERK2 cascade	BP	mutant phenotype
positive regulation of cell population proliferation	BP	mutant phenotype
positive regulation of receptor signaling pathway via JAK-STAT	BP	mutant phenotype
positive regulation of tyrosine phosphorylation of STAT protein	BP	mutant phenotype
protein autophosphorylation	BP	direct assay
signal transduction	BP	direct assay
basolateral plasma membrane	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
plasma membrane	CC	direct assay
signaling receptor complex	CC	direct assay
epidermal growth factor receptor binding	MF	physical interaction
neuregulin receptor activity	MF	direct assay
protein homodimerization activity	MF	physical interaction
protein tyrosine kinase activity	MF	direct assay
transcription cis-regulatory region binding	MF	mutant phenotype
transmembrane receptor protein tyrosine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 2,839 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERBB4	NRG1	P98202	955
ERBB4	NRG2	O14511	900
ERBB4	NRG4	Q8WWG1	881
ERBB4	NRG3	P56975	878
ERBB4	EGF	P01133	829
ERBB4	ERBB2	P04626	772
ERBB4	ERBB3	P21860	742
ERBB4	PVALB	P20472	728
ERBB4	PIK3CA	P42336	719
ERBB4	BTC	P35070	718
ERBB4	DISC1	Q9NRI5	712
ERBB4	HBEGF	Q99075	702
ERBB4	TGFA	P01135	679
ERBB4	PIK3CG	P48736	676
ERBB4	PIK3CD	O00329	675
ERBB4	PIK3CB	P42338	675

IntAct

Human interaction partners of ERBB4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 168 partners by confidence:

Partner	Interaction type	MIscore	Records
ERBB2	physical association	0.820	4
DLG4	physical association	0.740	9
EGFR	proximity	0.650	3
SHC1	direct interaction	0.610	7
DLG1	physical association	0.610	4
DLG3	direct interaction	0.590	4
ERBB3	physical association	0.590	4
DLG2	direct interaction	0.590	3
ITCH	physical association	0.590	3
LRIG1	physical association	0.590	3
LRRC7	physical association	0.590	2
BYSL	direct interaction	0.580	1
GRB2	physical association	0.570	7
PTPN11	physical association	0.570	2
S100A4	direct interaction	0.560	4
TROAP	association	0.560	3
CFL1	physical association	0.550	2
HDAC6	physical association	0.550	2
NRG1	direct interaction	0.540	3
HSP90AB1	physical association	0.520	2
PATJ	direct interaction	0.440	7
GRIP1	direct interaction	0.440	5
GRIP2	direct interaction	0.440	5
MAGI2	direct interaction	0.440	5
ABL2	direct interaction	0.440	4
IL16	direct interaction	0.440	3
MPDZ	direct interaction	0.440	3
NHERF4	direct interaction	0.440	3
PDZK1	direct interaction	0.440	3
YAP1	direct interaction	0.440	3

BioGRID (280 interactions; top human partners by supporting records): DLG4 (Two-hybrid; 8 records), YAP1 (Reconstituted Complex; 8 records), EGFR (FRET; 7 records), ERBB2 (Two-hybrid; 6 records), ITCH (Affinity Capture-Western; 6 records), LRIG1 (Affinity Capture-Western; 5 records), WWOX (Reconstituted Complex; 5 records), WWP1 (Affinity Capture-Western; 5 records), PTPN11 (Biochemical Activity; 4 records), SHC1 (Affinity Capture-MS; 4 records), BYSL (Reconstituted Complex; 3 records), FYN (Two-hybrid; 3 records), GRB2 (Affinity Capture-Western; 3 records), LRIG3 (Affinity Capture-Western; 3 records), NEDD4 (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 31 of 46 signaling interactions:

A	Effect	B	Mechanism
NRG1	up-regulates	ERBB4	binding
NRG2	up-regulates	ERBB4	binding
NRG3	up-regulates	ERBB4	binding
NRG4	up-regulates	ERBB4	binding
LRIG1	down-regulates	ERBB4	ubiquitination
EPGN	up-regulates	ERBB4	binding
ERBB4	up-regulates	GRB2	binding
ERBB4	up-regulates	PIK3CA	binding
ERBB4	up-regulates	PIK3CB	binding
ERBB4	up-regulates	PIK3CD	binding
ERBB4	up-regulates	PIK3CG	binding
ERBB4	up-regulates	SHC3	relocalization
ERBB4	up-regulates	STAT5A	binding
BTC	up-regulates	ERBB4	binding
ERBB4	up-regulates	CBL	binding
EREG	up-regulates	ERBB4	binding
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide	down-regulates	ERBB4	“chemical inhibition”
dacomitinib	down-regulates	ERBB4	“chemical inhibition”
LRIG1	down-regulates	ERBB4
LRIG3	up-regulates	ERBB4
ERBB4	up-regulates	PI3K	binding
afatinib	“down-regulates activity”	ERBB4	“chemical inhibition”
Neuregulin	up-regulates	ERBB4	binding
ITCH	“down-regulates quantity by destabilization”	ERBB4	polyubiquitination
MAPK3	“down-regulates activity”	ERBB4	phosphorylation
YAP/TAZ	“up-regulates activity”	ERBB4	binding
CDK5	“up-regulates activity”	ERBB4	phosphorylation
ERBB4	“up-regulates activity”	STAT5A	phosphorylation
ERBB2	up-regulates	ERBB4	binding
HBEGF	up-regulates	ERBB4	binding
ITCH	“down-regulates quantity by destabilization”	ERBB4	ubiquitination

Protein complexes (CORUM) (8)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

8 complexes by size:

Complex	Subunits	Members
★ ERBB2-ERBB4-NRG1 complex	3	NRG1, ERBB2, ERBB4
★ BTC-ERBB2-ERBB4 complex	3	BTC, ERBB2, ERBB4
★ ERBB4-NRG1 complex	2	ERBB4, NRG1
★ BTC-ERBB4 complex	2	BTC, ERBB4
★ ERBB4-YAP1 complex	2	ERBB4, YAP1
★ ERBB4-STAT5A complex	2	ERBB4, STAT5A
★ ERBB4-TRIM28 complex	2	ERBB4, TRIM28
★ ERBB4-ESR1 complex	2	ESR1, ERBB4

Ligand–receptor pairs (CellPhoneDB) (7)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

7 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
HBEGF	receptor	Signaling by Epidermal growth factor
NRG4	receptor	Signaling by Neuregulin
NRG1	receptor	Signaling by Neuregulin
NRG3	receptor	Signaling by Neuregulin
NRG2	receptor	Signaling by Neuregulin
BTC	receptor	Signaling by Betacellulin
EREG	receptor	Signaling by Epidermal growth factor

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 168 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
Signaling by ERBB2 TMD/JMD mutants	9	37.6×	2e-10
PI3K events in ERBB2 signaling	6	35.4×	5e-07
Signaling by ERBB2 ECD mutants	6	35.4×	5e-07
Signaling by ERBB2 KD Mutants	9	33.4×	5e-10
SHC1 events in ERBB2 signaling	8	33.4×	5e-09
Negative regulation of NMDA receptor-mediated neuronal transmission	7	33.4×	6e-08
ERBB2 Regulates Cell Motility	5	31.3×	1e-05
Downregulation of ERBB2 signaling	9	30.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	40.0×	9e-13
peptidyl-tyrosine dephosphorylation	7	38.8×	1e-07
protein localization to synapse	6	28.7×	7e-06
receptor clustering	7	27.3×	1e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	8	24.8×	2e-07
epidermal growth factor receptor signaling pathway	15	23.2×	1e-13
protein dephosphorylation	11	15.2×	7e-08
establishment of cell polarity	6	14.4×	3e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ErbB4 (HER4) is one of the four members in the EGFR subfamily of receptor tyrosine kinases. Ligands include EGF, epiregulin, betacellulin and the neuregulins (Sundvall et. al.). Of these, NRG3 and NRG4 exclusively bind HER4 (Hynes et. al.). Mutations in ERBB4 have been identified in various cancer types including melanoma, lung adenocarcinoma and medulloblastoma. A therapeutic value of these aberrations still remains unknown (Arteaga et. al.).

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 10 cancer types — BLCA, BRCA, CCRCC, CHOL, COADREAD, ESCA, HCC, MEL, PRAD, STAD.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for ERBB4: 792 ClinVar records (12 pathogenic / likely pathogenic); 3 CIViC cancer variants; 66 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	9
Uncertain significance	364
Likely benign	240
Benign	114

Top pathogenic / likely-pathogenic (12)

Showing all 12 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2208868	NM_005235.3(ERBB4):c.1015_1034del (p.Thr339fs)	Pathogenic	criteria provided, single submitter	1
2229731	NM_005235.3(ERBB4):c.1776dup (p.Cys593fs)	Pathogenic	criteria provided, single submitter	1
520885	NM_005235.3(ERBB4):c.119_120del (p.Leu39_Ser40insTer)	Likely pathogenic	criteria provided, single submitter	1
976654	NM_005235.3(ERBB4):c.3814G>A (p.Gly1272Arg)	Likely pathogenic	criteria provided, single submitter	1
3896859	NM_005235.3(ERBB4):c.3183+2T>C	Likely pathogenic	criteria provided, single submitter	1
4250421	NM_005235.3(ERBB4):c.883+1G>A	Likely pathogenic	criteria provided, single submitter	1
4250422	NM_005235.3(ERBB4):c.82+1G>A	Likely pathogenic	criteria provided, single submitter	1
4618670	NM_005235.3(ERBB4):c.29G>A (p.Trp10Ter)	Likely pathogenic	criteria provided, single submitter	1
4880190	NC_000002.12:g.211992663_212835430del	Likely pathogenic	criteria provided, single submitter	1
64625	NM_005235.3(ERBB4):c.2780G>A (p.Arg927Gln)	Pathogenic	no assertion criteria provided	2
638628	NM_005235.3(ERBB4):c.785G>A (p.Cys262Tyr)	Likely pathogenic	no assertion criteria provided	1
441579	GRCh37/hg19 2q34(chr2:212384649-214064185)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ERBB4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 5,736):

Position(s)	Effect	Δscore	Sites
2:211386851–211386852	donor_loss	1.0000	5
2:211386891	donor_gain	1.0000
2:211387151–211387152	acceptor_loss	1.0000	5
2:211387157	acceptor_gain	1.0000
2:211387168	acceptor_gain	1.0000
2:211420439–211420440	donor_loss	1.0000	3
2:211420612	acceptor_gain	1.0000
2:211420613	acceptor_loss	1.0000
2:211422005–211422006	donor_loss	1.0000	3
2:211422105–211422106	acceptor_loss	1.0000	6

AlphaMissense

4,075 missense substitutions predicted likely pathogenic (of 8,641 scored), across 861 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M977	9	0.995	1.000
M958	9	0.993	1.000
M951	9	0.991	1.000
M831	9	0.975	0.998
M772	9	0.964	0.998
M953	9	0.958	1.000
M887	9	0.947	1.000
M914	9	0.942	0.999
M882	9	0.853	0.988
D861	8	0.999	1.000
D902	8	0.999	1.000
H841	8	0.998	0.999
N848	8	0.997	0.999
D585	8	0.996	0.999
D843	8	0.994	1.000
D980	8	0.994	1.000
N122	8	0.992	1.000
N152	8	0.991	0.999
D165	8	0.991	0.998
F967	8	0.991	1.000

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Breast Invasive Carcinoma)

Disease associations

OMIM: gene MIM:600543 | disease phenotypes: MIM:615515

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
amyotrophic lateral sclerosis type 19	Strong	Autosomal dominant	3
intellectual disability	Strong	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 19	Limited	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Adult-onset neurological disorders	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Neurodegenerative disorders, adult onset	green
Paediatric disorders	green

Mondo (4): amyotrophic lateral sclerosis type 19 (MONDO:0014223), NK-cell enteropathy (MONDO:0016996), amyotrophic lateral sclerosis (MONDO:0004976), intellectual disability (MONDO:0001071)

Orphanet (2): Amyotrophic lateral sclerosis (Orphanet:803), NK-cell enteropathy (Orphanet:263665)

HPO phenotypes

53 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002505	Loss of ambulation
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003693	Distal amyotrophy
HP:0004326	Cachexia
HP:0007340	Lower limb muscle weakness
HP:0007354	Amyotrophic lateral sclerosis
HP:0007373	Motor neuron atrophy
HP:0008955	Progressive distal muscular atrophy
HP:0009027	Foot dorsiflexor weakness
HP:0012378	Fatigue
HP:0012473	Tongue atrophy
HP:0012531	Pain
HP:0012764	Orthopnea
HP:0025425	Laryngospasm
HP:0030192	Fatigable weakness of bulbar muscles
HP:0030195	Fatigable weakness of swallowing muscles
HP:0030196	Fatigable weakness of respiratory muscles
HP:0030878	Abnormality on pulmonary function testing
HP:0031993	Hoffmann sign
HP:0033683	Jaw hyperreflexia
HP:0100543	Cognitive impairment

GWAS associations

showing 30 of 66 associations:

Study	Trait	p-value
GCST005984_26	Glomerular filtration rate	5e-15
GCST012355_5	Depression	3e-14
GCST001457_1	Breast cancer	9e-14
GCST010796_3056	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-13
GCST009391_222	Metabolite levels	8e-13
GCST003144_2	Polycystic ovary syndrome	1e-12
GCST010796_3055	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-12
GCST012490_237	Femur bone mineral density x serum urate levels interaction	5e-12
GCST010796_3054	Electrocardiogram morphology (amplitude at temporal datapoints)	9e-12
GCST006414_104	Atrial fibrillation	1e-11
GCST004495_98	BMI (adjusted for smoking behaviour)	3e-11
GCST004904_20	Body mass index	3e-11
GCST008972_132	Urate levels	3e-11
GCST002783_599	Body mass index	5e-11
GCST006624_69	Systolic blood pressure	8e-11
GCST90000514_24	Gastroesophageal reflux disease	9e-11
GCST002783_220	Body mass index	1e-10
GCST004497_77	Body mass index (joint analysis main effects and smoking interaction)	3e-10
GCST011956_106	Systemic lupus erythematosus	3e-10
GCST006947_54	Feeling fed-up	4e-10
GCST90000047_213	Age at first sexual intercourse	7e-10
GCST004499_29	BMI in non-smokers	1e-9
GCST009523_14	Household income	1e-9
GCST009524_255	Household income (MTAG)	1e-9
GCST009524_256	Household income (MTAG)	1e-9
GCST010796_3053	Electrocardiogram morphology (amplitude at temporal datapoints)	1e-9
GCST010988_330	Adult body size	1e-9
GCST009463_7	Loneliness	2e-9
GCST009523_17	Household income	2e-9
GCST008971_19	Urate levels	3e-9

EFO canonical traits (from GWAS)

23 canonical traits:

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004365	personality trait
EFO:0008343	sex interaction measurement
EFO:0005937	longitudinal BMI measurement
EFO:0004340	body mass index
EFO:0004318	smoking behavior
EFO:0004682	QT interval
EFO:0008255	particulate matter air pollution measurement
EFO:0004337	intelligence
EFO:0006335	systolic blood pressure
EFO:0007865	loneliness measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0008392	triiodothyronine measurement
EFO:0004531	urate measurement
EFO:0004886	intracranial volume measurement
EFO:0010542	ureidopropionic acid measurement
EFO:0009767	glycine measurement
EFO:0009774	serine measurement
EFO:0009695	household income
EFO:0004327	electrocardiography
EFO:0007006	depressive symptom measurement
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363049 (PROTEIN FAMILY), CHEMBL3009 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ERBB4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

7 curated-mechanism drugs:

Drug	Modality	Max phase
AFATINIB DIMALEATE	Small molecule	4
DACOMITINIB	Small molecule	4
NERATINIB	Small molecule	4
CANERTINIB DIHYDROCHLORIDE	Small molecule	3
BMS-690514	Small molecule	2
AC-480	Small molecule	1
JNJ-26483327	Small molecule	1

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes ERBB4 — the drug acts on the assembly or class, not necessarily on this subunit alone.

4 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
VANDETANIB	Epidermal growth factor receptor	4	4
POZIOTINIB	Epidermal growth factor receptor	4	3
TARLOXOTINIB	Epidermal growth factor receptor	4	2
KBP5209	Epidermal growth factor receptor	4	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 430,772 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

47 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL2105712	AFATINIB DIMALEATE	4	3,441
CHEMBL2105719	DACOMITINIB	4	825
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,949
CHEMBL180022	NERATINIB	4	9,891
CHEMBL3707348	ACALABRUTINIB	4	4,772
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL3545311	BRIGATINIB	4	5,988
CHEMBL5416410	DASATINIB	4	674
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL939	GEFITINIB	4	119,425
CHEMBL1873475	IBRUTINIB	4	8,363
CHEMBL554	LAPATINIB	4	70,425
CHEMBL608533	MIDOSTAURIN	4	7,641
CHEMBL4650319	MOBOCERTINIB	4	1,002
CHEMBL4085457	RITLECITINIB	4	784
CHEMBL4071161	TIRABRUTINIB	4	2,261
CHEMBL24828	VANDETANIB	4	43,290
CHEMBL3936761	ZANUBRUTINIB	4	2,664
CHEMBL31965	CANERTINIB	3
CHEMBL545315	CANERTINIB DIHYDROCHLORIDE	3
CHEMBL483158	ALISERTIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL4072833	EVOBRUTINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL4483575	REMIBRUTINIB	3
CHEMBL587723	AEE-788	2
CHEMBL1947204	ALLITINIB	2
CHEMBL4114766	ATUZABRUTINIB	2
CHEMBL513909	BI-2536	2
CHEMBL4297674	BRANEBRUTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL215152	DEFOSBARASERTIB	2
CHEMBL1230609	FORETINIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL1980715	LAUROGUADINE	2
CHEMBL607707	PELITINIB	2
CHEMBL475251	R-406	2
CHEMBL363648	TAK-715	2
CHEMBL230011	TG100-115	2
CHEMBL2103842	VARLITINIB	2
CHEMBL1645462	AC-480	1
CHEMBL3109738	JNJ-26483327	1
CHEMBL1980391	RG-1530	1
CHEMBL1614725	TAK-285	1

Clinical evidence (CIViC)

Drug × variant × indication, from 4 curated evidence items; also 1 prognostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

4 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
ERBB4 Mutation	Lapatinib	Melanoma	Sensitivity/Response	CIViC D	EID770
ERBB4 EXPRESSION	Trastuzumab	HER2 Positive Breast Cancer	Resistance	CIViC D	EID868
ERBB4 EXPRESSION	Lapatinib	Breast Cancer	Resistance	CIViC D	EID869
ERBB4 NUCLEAR TRANSLOCATION	Trastuzumab	Breast Cancer	Resistance	CIViC D	EID867

CIViC curated variants (3)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

Mutation (gain of function variant,transcript variant), NUCLEAR TRANSLOCATION, EXPRESSION.

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs3942465	clozapine	Toxicity	Allele C is associated with increased likelihood of dry mouth when treated with clozapine as compared to allele T.	PMID:38634369

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type I RTKs: ErbB (epidermal growth factor) receptor family

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
EGFR/ErbB-2/ErbB-4 inhibitor	Inhibition	9.3	pIC50
allitinib	Inhibition	9.1	pIC50
pirotinib	Inhibition	8.72	pIC50
compound 38 [PMID: 24915291]	Inhibition	8.48	pIC50
ibrutinib	Inhibition	8.47	pIC50
betacellulin		8.44	pIC50
acalabrutinib	Inhibition	7.8	pIC50
poziotinib	Inhibition	7.63	pIC50
AEE788	Inhibition	7.59	pIC50
WZ4002	Inhibition	7.55	pKd
compound 9 [PMID: 26006010]	Inhibition	7.19	pIC50
dacomitinib	Inhibition	7.13	pIC50
BMS-599626	Inhibition	6.72	pIC50
tucatinib	Inhibition	6.51	pIC50
neuregulin-1		6.29	pIC50
xiliertinib	Inhibition	6.15	pIC50

Binding affinities (BindingDB)

597 measured of 800 human assays (802 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
PD153035 Analog	IC50	0.006 nM
CHEMBL3808884	EC50	0.04 nM
CHEMBL3357639	IC50	0.26 nM
N-[4-[(3-chloro-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-2-butynamide	IC50	0.3 nM
CHEMBL3357642	IC50	0.31 nM
CHEMBL3818547	IC50	0.31 nM
CHEMBL3818062	IC50	0.35 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
AP-26113	IC50	0.37 nM
CHEMBL3818015	IC50	0.38 nM
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(6-methyl- 6-azaspiro[2.5]octan-1- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.39 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
1-[(3S)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	IC50	0.4 nM	US-8476284: Inhibitors of Bruton’s tyrosine kinase
CHEMBL3758602	KI	0.4 nM
CHEMBL3797606	IC50	0.4 nM
N-[4-[(3-chloro-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methyl-1-piperazinyl)-2-pentynamide	IC50	0.5 nM
CHEMBL3357643	IC50	0.53 nM
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(7-methyl- 7-azaspiro[3.5]nonan-2- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.56 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-2-propynamide	IC50	0.6 nM
CHEMBL5189379	IC50	0.6 nM
(6,7-Diethoxy-quinazolin-4-yl)-(3-iodo-phenyl)-amine	IC50	0.64 nM
N-[4-(3-chloro-4- fluorophenylamino)-7-(2- ((1R,5S,6S)-3-methyl-3- azabicyclo[3.1.0]hexan-6- ylethoxy)quinazolin-6-yl]- acrylamide	IC50	0.66 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
CHEMBL3814257	IC50	0.662 nM
CHEMBL3798501	IC50	0.7 nM
CHEMBL3290148	IC50	0.71 nM
CHEMBL3818563	IC50	0.71 nM
N-[3-[[2-[4-(4-methylpiperazin-1-yl)anilino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenyl]prop-2-enamide	IC50	0.79 nM	US-9586965: Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases
N-[4-(3-chloro-4- fluorophenylamino)-7-(2-(3-methyl- 3-azabicyclo[3.2.1]octan-8- yl)ethoxy)quinazolin-6-yl]- acrylamide	IC50	0.8 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
1-[(2R)-2-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	IC50	0.8 nM	US-20240317756: INHIBITORS OF BRUTON’S TYROSINE KINASE
CHEMBL3814959	IC50	0.803 nM
CHEMBL3818289	IC50	0.83 nM
CHEMBL3814211	IC50	0.854 nM
BI 1482694	IC50	0.9 nM
N-[4-[(3-chloro-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-5-(1-piperidinyl)-2-pentynamide	IC50	0.9 nM
CHEMBL6165880	IC50	0.9 nM
N-[4-(3-chloro-4- fluorophenylamino)-7-(8-methyl-1- oxa-8-azaspiro[4.5]decan-2- ylmethoxy)quinazolin-6-yl]- acrylamide	IC50	0.93 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((8-methyl-1- oxa-8-azaspiro[4.5]decan-3- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
N-[4-(3-chloro-4- fluorophenylamino)-7-((7-methyl-7- azaspiro[3.5]nonan-2- yl)methoxy)quinazolin-6-yl]- acrylamide	IC50	1 nM	US-10507209: Quinazoline derivatives substituted by aniline, preparation method and use thereof
CHEMBL3357640	IC50	1 nM
CHEMBL2031296	IC50	1 nM
CHEMBL3968417	IC50	1 nM
CHEMBL3765263	IC50	1.1 nM
CHEMBL3814956	IC50	1.1 nM
N-[4-[(3-bromo-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methyl-1-piperazinyl)-2-pentynamide	IC50	1.1 nM
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9181263: Inhibitors of bruton’s tyrosine kinase
N-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]-7-oxopteridin-8-yl]phenyl]prop-2-enamide	IC50	1.2 nM	US-9670213: Pteridine ketone derivative and applications thereof as EGFR, BLK, and FLT3 inhibitor
CHEMBL3818364	IC50	1.2 nM
CHEMBL4647228	IC50	1.2 nM
N-[4-[(3-chloro-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-5-(4-morpholinyl)-2-pentynamide	IC50	1.3 nM
CHEMBL3818115	IC50	1.3 nM
N-[4-[(3-Chloro-4-fluorophenyl)amino]-6-quinazolinyl]-4-hydroxy-2-butynamide	IC50	1.4 nM

ChEMBL bioactivities

499 potent at pChembl≥5 of 506 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	IC50	0.03	nM	CHEMBL4646030
10.00	IC50	0.1	nM	IBRUTINIB
9.72	IC50	0.19	nM	CHEMBL4642574
9.60	IC50	0.25	nM	IBRUTINIB
9.35	IC50	0.45	nM	CHEMBL4517633
9.30	IC50	0.5	nM	CHEMBL203644
9.22	IC50	0.6	nM	CHEMBL4211949
9.22	IC50	0.6	nM	IBRUTINIB
9.16	IC50	0.69	nM	CHEMBL2387001
9.10	IC50	0.8	nM	CHEMBL437890
9.10	IC50	0.8	nM	ALLITINIB
9.05	IC50	0.89	nM	CHEMBL2387000
9.04	Kd	0.91	nM	IBRUTINIB
9.00	IC50	1	nM	CHEMBL3959248
9.00	IC50	1	nM	CHEMBL204638
9.00	IC50	1	nM	CHEMBL203661
9.00	IC50	1	nM	AFATINIB
8.92	IC50	1.2	nM	CHEMBL2386999
8.92	IC50	1.2	nM	CHEMBL203599
8.92	IC50	1.2	nM	CHEMBL4647228
8.80	IC50	1.58	nM	ZANUBRUTINIB
8.80	IC50	1.6	nM	CHEMBL5182567
8.77	IC50	1.7	nM	CHEMBL202360
8.77	IC50	1.7	nM	CHEMBL3622673
8.74	IC50	1.8	nM	CHEMBL205059
8.74	IC50	1.8	nM	IBRUTINIB
8.70	IC50	2	nM	AEE-788
8.70	IC50	2	nM	CHEMBL3890186
8.70	IC50	2	nM	CHEMBL3896779
8.70	IC50	2	nM	CHEMBL5208454
8.62	IC50	2.4	nM	CHEMBL203645
8.62	IC50	2.4	nM	CHEMBL4075917
8.62	Kd	2.4	nM	IBRUTINIB
8.62	Kd	2.4	nM	NERATINIB
8.60	Ki	2.512	nM	CHEMBL1981725
8.57	IC50	2.7	nM	IBRUTINIB
8.52	IC50	3	nM	CHEMBL3086102
8.52	IC50	3	nM	CHEMBL3932176
8.52	IC50	3	nM	CHEMBL3970330
8.52	IC50	3	nM	CHEMBL3958482
8.52	IC50	3	nM	CHEMBL3986103
8.52	IC50	3	nM	CHEMBL3949347
8.52	IC50	3	nM	CHEMBL3977504
8.52	IC50	3	nM	CHEMBL3981551
8.52	IC50	3	nM	CHEMBL4473365
8.49	IC50	3.2	nM	CHEMBL3647967
8.49	IC50	3.2	nM	CHEMBL4068839
8.48	IC50	3.3	nM	CHEMBL3290148
8.48	IC50	3.3	nM	CHEMBL4860202
8.48	IC50	3.3	nM	MOBOCERTINIB

PubChem BioAssay actives

376 with measured affinity, of 2212 total; 50 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
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2S)-2,3-dihydroxypropoxy]quinolin-6-yl]-2-(dithiolan-4-yl)acetamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	<0.0001	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2R)-2,3-dihydroxypropoxy]quinolin-6-yl]-2-(dithiolan-4-yl)acetamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0002	uM
Ibrutinib	1615370: Inhibition of human HER4 using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0003	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-[(2S)-2,3-dihydroxypropoxy]quinolin-6-yl]dithiolane-4-carboxamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0004	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0005	uM
N-[(7S)-4-amino-6-methylidene-5-(4-phenoxyphenyl)-7,8-dihydropyrimido[5,4-b]pyrrolizin-7-yl]prop-2-enamide	1375524: Inhibition of recombinant human ErbB4 using Poly(Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	ic50	0.0006	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-methoxy-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0007	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0008	uM
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]prop-2-enamide	2161300: Inhibition of ErbB4 (unknown origin) using poly(Glu-Tyr) at 4:1 ratio as substrate in presence of ATP incubated for 60 mins by ELISA	ic50	0.0008	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0009	uM
Afatinib	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0010	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0010	uM
N-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-morpholin-4-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0010	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0010	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-(4-methylpiperazin-1-yl)pent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0012	uM
N-[4-(3-chloro-4-fluoroanilino)-7-[2-(6-methyl-6-azaspiro[2.5]octan-2-yl)ethoxy]quinolin-6-yl]prop-2-enamide	1664190: Inhibition of HER4 (unknown origin) in presence of radiolabelled gammaATP by radioisotope filter binding assay	ic50	0.0012	uM
1-[3-(4-amino-7-cyclopentylpyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl]-3-(2,4-dichlorophenyl)urea	748805: Inhibition of human EGFR extracellular domain/TIE2 intracellular domain transfected in mouse NIH/3T3 cells assessed as phosphotyrosine level preincubated for 60 mins followed by EGF stimulation by DELFIA assay	ic50	0.0012	uM
Zanubrutinib	1615370: Inhibition of human HER4 using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0016	uM
N-[4-[(3-bromo-1H-indol-5-yl)amino]quinazolin-6-yl]prop-2-enamide	1904485: Inhibition of HER4 (unknown origin)	ic50	0.0016	uM
N-[4-(3-bromoanilino)quinazolin-6-yl]prop-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0017	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-5-piperidin-1-ylpent-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0018	uM
6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	710623: Inhibition of EGFR2	ic50	0.0020	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0020	uM
(E)-N-[4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0020	uM
N-[4-[(3-bromo-1H-indol-5-yl)amino]quinazolin-6-yl]-3-chloropropanamide	1904485: Inhibition of HER4 (unknown origin)	ic50	0.0020	uM
N-[4-(3-chloro-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]hex-2-ynamide	260897: Inhibition of erbB4 fusion protein expressed in baculovirus by ELISA	ic50	0.0024	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450713: Inhibition of recombinant ErbB4 (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0024	uM
Neratinib	624815: Binding constant for ERBB4 kinase domain	kd	0.0024	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-4-(dimethylamino)-N-[4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-4-(4-methylpiperazin-1-yl)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[4-(benzenesulfonamido)anilino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
N-[5-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide	1584367: Inhibition of recombinant N-terminal GST-tagged human ErbB4 cytoplasmic domain expressed in baculovirus expression system by Z-LYTE assay	ic50	0.0030	uM
(E)-N-[7-methoxy-4-(4-phenoxyanilino)quinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0030	uM
7-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-3-phenyl-1-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]-4H-pyrimido[4,5-d]pyrimidin-2-one	1053594: Inhibition of EGFR L851Q mutant (unknown origin)	ic50	0.0030	uM
1-[(3R)-3-[4-amino-3-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	1481346: Inhibition of recombinant human N-terminal GST-tagged ERBB4 cytoplasmic domain (708 to 993 residues) expressed in baculovirus by Z’-LYTE assay	ic50	0.0032	uM
Mobocertinib	1935456: Inhibition of mouse EGFR L858R mutant stably expressed in mouse BaF3 cells assessed as cell viability incubated for 3 days by Cell Titer-Glo assay	ic50	0.0033	uM
5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-phenylmethoxyphenyl)imidazo[2,1-b][1,3]thiazole	1772926: Inhibition of ErbB4 in human T47D cells assessed as suppression of neuregulin 1-induced autophosphorylation incubated for 90 mins by sandwich ELISA	ic50	0.0033	uM
2-methyl-N-[2-[3-[[2-(prop-2-enoylamino)acetyl]amino]anilino]pyrimidin-5-yl]-5-[[3-(trifluoromethyl)benzoyl]amino]benzamide	1155503: Inhibition of HER4 (unknown origin) after 1 hr by HTRF assay	ic50	0.0033	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-(4-methylpiperazin-1-yl)but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-4-(dimethylamino)-N-[4-[4-(pyridin-2-ylmethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[4-(pyridin-2-ylmethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[(1-benzylindazol-5-yl)amino]-7-ethoxyquinazolin-6-yl]-4-[(2S,6R)-2,6-dimethylpiperazin-1-yl]but-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM
(E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-7-ethoxyquinazolin-6-yl]-4-pyrrolidin-1-ylbut-2-enamide	1315980: Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA	ic50	0.0040	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, increases reaction, affects cotreatment, decreases expression, decreases reaction	4
Valproic Acid	decreases expression, increases expression	4
Aflatoxin B1	decreases expression, decreases methylation	4
Arsenic Trioxide	increases expression	3
sodium arsenite	affects acetylation, affects methylation, decreases expression	2
Arsenic	affects expression, affects methylation	2
Doxorubicin	decreases expression, affects cotreatment, affects response to substance	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Tretinoin	increases expression, decreases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
Particulate Matter	increases abundance, affects expression, decreases methylation	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases cleavage	1
sulindac sulfide	affects cleavage	1
ochratoxin A	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
oxophenylarsine	increases cleavage, increases phosphorylation	1
bisindolylmaleimide I	decreases reaction, increases cleavage	1
pervanadate	decreases reaction, increases cleavage	1
27-hydroxycholesterol	decreases expression	1
batimastat	decreases reaction, increases cleavage	1
CGP 52608	affects binding, increases reaction	1
6-(methylamino)pyrido(3,4-d)pyrimidine	decreases activity	1
monomethylarsonous acid	affects acetylation, affects methylation	1
ponatinib	decreases activity	1
Irinotecan	increases expression	1

ChEMBL screening assays

591 unique, capped per target: 579 binding, 8 admet, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034137	Binding	Inhibition of EGFR E746-A750del mutant at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — *J Med Chem*
CHEMBL1963833	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ERBB4	PubChem BioAssay data set
CHEMBL4023735	ADMET	Inhibition of recombinant human cytoplasmic GST-tagged ERBB4 expressed in baculovirus at 1 uM by Z’-LYTE assay	Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development. — *J Med Chem*

Cellosaurus cell lines

13 cell lines: 9 cancer cell line, 3 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1726	SW684	Cancer cell line	Male
CVCL_B8FH	Abcam HCT 116 ERBB4 KO	Cancer cell line	Male
CVCL_B8VD	Abcam MCF-7 ERBB4 KO	Cancer cell line	Female
CVCL_B9HQ	Abcam A-549 ERBB4 KO	Cancer cell line	Male
CVCL_D9EH	Ubigene HEK293 ERBB4 KO	Transformed cell line	Female
CVCL_E0CS	Ubigene HeLa ERBB4 KO	Cancer cell line	Female
CVCL_E4W9	KOLF2.1J ERBB4 PTC PTC/PTC	Induced pluripotent stem cell	Male
CVCL_E5GM	SP-01-CL	Cancer cell line	Male
CVCL_E5GN	SP-01-OT-CL	Cancer cell line	Male
CVCL_E7KY	KOLF2.1J ERBB4 R927Q SNV/SNV	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00542412	Phase 4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	Phase 4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	Phase 4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	Phase 4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	Phase 4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	Phase 4	ACTIVE_NOT_RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	Phase 3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	Phase 3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	Phase 3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	Phase 3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	Phase 3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	Phase 3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	Phase 3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	Phase 3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	Phase 3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	Phase 3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	Phase 3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	Phase 3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	Phase 3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	Phase 3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	Phase 3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	Phase 3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	Phase 3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	Phase 3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	Phase 3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	Phase 3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	Phase 3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	Phase 3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	Phase 3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	Phase 3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	Phase 3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	Phase 3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	Phase 3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	Phase 3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	Phase 3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	Phase 3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	Phase 3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	Phase 3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	Phase 3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	Phase 3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04577404	Phase 3	COMPLETED	Safety Extension Study of Oral Edaravone Administered in Subjects With Amyotrophic Lateral Sclerosis (ALS)
NCT04745299	Phase 3	COMPLETED	Evaluation the Efficacy and Safety of Mutiple Lenzumestrocel (Neuronata-R® Inj.) Treatment in Patients With ALS
NCT04768972	Phase 3	ACTIVE_NOT_RECRUITING	FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)
NCT04944784	Phase 3	TERMINATED	A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT05021536	Phase 3	UNKNOWN	Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment
NCT05151471	Phase 3	TERMINATED	Efficacy and Safety Extension Study of Oral Edaravone Administered in Subjects With ALS
NCT05178810	Phase 3	COMPLETED	Study to Investigate the Efficacy and Safety of FAB122 (Daily Oral Edaravone) in Patients With Amyotrophic Lateral Sclerosis
NCT05193994	Phase 3	TERMINATED	Triumeq in Amyotrophic Lateral Sclerosis
NCT05442775	Phase 3	TERMINATED	A Phase 3, Open-Label Extension of COURAGE-ALS (CY 5031)
NCT05568615	Phase 3	COMPLETED	Extension Study Following the Studies MT-1186-A03 or A04 to Evaluate the Safety of Oral Edaravone in Subjects With ALS
NCT05619783	Phase 3	COMPLETED	Extension Study Evaluating The Safety And Tolerability of AMX0035
NCT05753852	Phase 3	UNKNOWN	Open Label Extension of TUDCA-ALS Study
NCT05866926	Phase 3	TERMINATED	Study to Investigate the Long-term Safety of FAB122 in Patients With Amyotrophic Lateral Sclerosis
NCT06008249	Phase 3	TERMINATED	Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
NCT06658977	Phase 3	TERMINATED	RolloverTreatment With Triumeq for People With ALS Following the Lighthouse II Trial
NCT06973629	Phase 3	NOT_YET_RECRUITING	Efficacy and Safety of MSC-NTF (NurOwn) in Participants With Early Symptomatic ALS and Moderate Disease Presentation in ALS (ENDURANCE STUDY)
NCT07174492	Phase 3	NOT_YET_RECRUITING	Efficacy and Safety of Masitinib in Combination With SoC Versus Placebo in the Treatment of ALS Patients
NCT07322003	Phase 3	RECRUITING	Pridopidine Phase 3 Study to Evaluate Efficacy and Safety in ALS
NCT00004771	Phase 2	COMPLETED	Phase II Study of Leuprolide and Testosterone for Men With Kennedy’s Disease or Other Motor Neuron Disease
NCT00005674	Phase 2	COMPLETED	Clinical Trial of Creatine in Amyotrophic Lateral Sclerosis [ALS]

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ERBB4 across ~30M SureChEMBL compounds — explore on Sugi Predict.