NRG4 (neuregulin 4)

Gene

• Entrez ID: 145957
• Gene name: Neuregulin 4
• Gene symbol: NRG4
• Synonyms (NCBI Gene): HRG4
• Chromosome: 15
• Chromosome location: 15q24.2
• Summary: The neuregulins, including NRG4, activate type-1 growth factor receptors (see EGFR; MIM 131550) to initiating cell-to-cell signaling through tyrosine phosphorylation (Harari et al., 1999 [PubMed 10348342]).[supplied by OMIM, Mar 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT024936	hsa-miR-215-5p	Microarray	19074876
MIRT026870	hsa-miR-192-5p	Microarray	19074876
MIRT454404	hsa-miR-6758-5p	PAR-CLIP	23592263
MIRT454403	hsa-miR-6856-5p	PAR-CLIP	23592263
MIRT454402	hsa-miR-6873-5p	PAR-CLIP	23592263
MIRT454400	hsa-miR-1321	PAR-CLIP	23592263
MIRT454401	hsa-miR-4739	PAR-CLIP	23592263
MIRT454399	hsa-miR-4756-5p	PAR-CLIP	23592263
MIRT454398	hsa-miR-5693	PAR-CLIP	23592263
MIRT454397	hsa-miR-194-3p	PAR-CLIP	23592263
MIRT454396	hsa-miR-4419a	PAR-CLIP	23592263
MIRT454395	hsa-miR-4510	PAR-CLIP	23592263
MIRT454394	hsa-miR-6127	PAR-CLIP	23592263
MIRT454393	hsa-miR-6129	PAR-CLIP	23592263
MIRT454392	hsa-miR-6130	PAR-CLIP	23592263
MIRT454391	hsa-miR-6133	PAR-CLIP	23592263
MIRT454390	hsa-miR-1914-3p	PAR-CLIP	23592263
MIRT454388	hsa-miR-5194	PAR-CLIP	23592263
MIRT454389	hsa-miR-6738-5p	PAR-CLIP	23592263
MIRT454387	hsa-miR-185-5p	PAR-CLIP	23592263
MIRT454386	hsa-miR-4306	PAR-CLIP	23592263
MIRT454385	hsa-miR-4644	PAR-CLIP	23592263
MIRT454384	hsa-miR-6878-5p	PAR-CLIP	23592263
MIRT454383	hsa-miR-6731-5p	PAR-CLIP	23592263
MIRT454382	hsa-miR-8085	PAR-CLIP	23592263
MIRT454381	hsa-miR-6881-5p	PAR-CLIP	23592263
MIRT454380	hsa-miR-4276	PAR-CLIP	23592263
MIRT454379	hsa-miR-30c-1-3p	PAR-CLIP	23592263
MIRT454378	hsa-miR-30c-2-3p	PAR-CLIP	23592263
MIRT454377	hsa-miR-6788-5p	PAR-CLIP	23592263
MIRT454404	hsa-miR-6758-5p	PAR-CLIP	23592263
MIRT454403	hsa-miR-6856-5p	PAR-CLIP	23592263
MIRT454402	hsa-miR-6873-5p	PAR-CLIP	23592263
MIRT454400	hsa-miR-1321	PAR-CLIP	23592263
MIRT454401	hsa-miR-4739	PAR-CLIP	23592263
MIRT454399	hsa-miR-4756-5p	PAR-CLIP	23592263
MIRT454398	hsa-miR-5693	PAR-CLIP	23592263
MIRT454397	hsa-miR-194-3p	PAR-CLIP	23592263
MIRT454396	hsa-miR-4419a	PAR-CLIP	23592263
MIRT454395	hsa-miR-4510	PAR-CLIP	23592263
MIRT454394	hsa-miR-6127	PAR-CLIP	23592263
MIRT454393	hsa-miR-6129	PAR-CLIP	23592263
MIRT454392	hsa-miR-6130	PAR-CLIP	23592263
MIRT454391	hsa-miR-6133	PAR-CLIP	23592263
MIRT454390	hsa-miR-1914-3p	PAR-CLIP	23592263
MIRT454388	hsa-miR-5194	PAR-CLIP	23592263
MIRT454389	hsa-miR-6738-5p	PAR-CLIP	23592263
MIRT454387	hsa-miR-185-5p	PAR-CLIP	23592263
MIRT454386	hsa-miR-4306	PAR-CLIP	23592263
MIRT454385	hsa-miR-4644	PAR-CLIP	23592263
MIRT454384	hsa-miR-6878-5p	PAR-CLIP	23592263
MIRT454383	hsa-miR-6731-5p	PAR-CLIP	23592263
MIRT454382	hsa-miR-8085	PAR-CLIP	23592263
MIRT454381	hsa-miR-6881-5p	PAR-CLIP	23592263
MIRT454380	hsa-miR-4276	PAR-CLIP	23592263
MIRT454379	hsa-miR-30c-1-3p	PAR-CLIP	23592263
MIRT454378	hsa-miR-30c-2-3p	PAR-CLIP	23592263
MIRT454377	hsa-miR-6788-5p	PAR-CLIP	23592263
MIRT1193951	hsa-miR-137	CLIP-seq
MIRT1193952	hsa-miR-27a	CLIP-seq
MIRT1193953	hsa-miR-27b	CLIP-seq
MIRT1193954	hsa-miR-3121-5p	CLIP-seq
MIRT1193955	hsa-miR-3123	CLIP-seq
MIRT1193956	hsa-miR-362-5p	CLIP-seq
MIRT1193957	hsa-miR-3925-5p	CLIP-seq
MIRT1193958	hsa-miR-4452	CLIP-seq
MIRT1193959	hsa-miR-4474-5p	CLIP-seq
MIRT1193960	hsa-miR-4494	CLIP-seq
MIRT1193961	hsa-miR-4639-5p	CLIP-seq
MIRT1193962	hsa-miR-4640-5p	CLIP-seq
MIRT1193963	hsa-miR-4659a-3p	CLIP-seq
MIRT1193964	hsa-miR-4659b-3p	CLIP-seq
MIRT1193965	hsa-miR-4670-3p	CLIP-seq
MIRT1193966	hsa-miR-4726-5p	CLIP-seq
MIRT1193967	hsa-miR-4732-5p	CLIP-seq
MIRT1193968	hsa-miR-4786-3p	CLIP-seq
MIRT1193969	hsa-miR-500b	CLIP-seq
MIRT1193970	hsa-miR-513a-5p	CLIP-seq
MIRT1193971	hsa-miR-629	CLIP-seq
MIRT1193972	hsa-miR-892a	CLIP-seq
MIRT2056239	hsa-miR-3661	CLIP-seq
MIRT2056240	hsa-miR-631	CLIP-seq
MIRT2056241	hsa-miR-758	CLIP-seq
MIRT2455456	hsa-miR-3065-5p	CLIP-seq
MIRT2455457	hsa-miR-3617	CLIP-seq
MIRT2455458	hsa-miR-4668-3p	CLIP-seq
MIRT2455459	hsa-miR-548u	CLIP-seq
MIRT2455460	hsa-miR-641	CLIP-seq
MIRT2582614	hsa-miR-1299	CLIP-seq
MIRT2582615	hsa-miR-3613-3p	CLIP-seq
MIRT2582616	hsa-miR-3672	CLIP-seq
MIRT2582617	hsa-miR-371-5p	CLIP-seq
MIRT2582618	hsa-miR-371b-5p	CLIP-seq
MIRT2582619	hsa-miR-4434	CLIP-seq
MIRT2582620	hsa-miR-4516	CLIP-seq
MIRT2582621	hsa-miR-4531	CLIP-seq
MIRT2582622	hsa-miR-4728-5p	CLIP-seq
MIRT2582623	hsa-miR-4782-5p	CLIP-seq
MIRT2582624	hsa-miR-4802-3p	CLIP-seq
MIRT2582625	hsa-miR-516b	CLIP-seq
MIRT2582626	hsa-miR-548a-5p	CLIP-seq
MIRT2582627	hsa-miR-548ab	CLIP-seq
MIRT2582628	hsa-miR-548ak	CLIP-seq
MIRT2582629	hsa-miR-548b-5p	CLIP-seq
MIRT2582630	hsa-miR-548c-5p	CLIP-seq
MIRT2582631	hsa-miR-548d-5p	CLIP-seq
MIRT2582632	hsa-miR-548h	CLIP-seq
MIRT2582633	hsa-miR-548i	CLIP-seq
MIRT2582634	hsa-miR-548j	CLIP-seq
MIRT2582635	hsa-miR-548k	CLIP-seq
MIRT2582636	hsa-miR-548l	CLIP-seq
MIRT2582637	hsa-miR-548n	CLIP-seq
MIRT2455459	hsa-miR-548u	CLIP-seq
MIRT2582638	hsa-miR-548w	CLIP-seq
MIRT2582639	hsa-miR-548y	CLIP-seq
MIRT2582640	hsa-miR-559	CLIP-seq
MIRT2582614	hsa-miR-1299	CLIP-seq
MIRT2582615	hsa-miR-3613-3p	CLIP-seq
MIRT2582616	hsa-miR-3672	CLIP-seq
MIRT2582617	hsa-miR-371-5p	CLIP-seq
MIRT2582618	hsa-miR-371b-5p	CLIP-seq
MIRT2582619	hsa-miR-4434	CLIP-seq
MIRT2582620	hsa-miR-4516	CLIP-seq
MIRT2582621	hsa-miR-4531	CLIP-seq
MIRT2582622	hsa-miR-4728-5p	CLIP-seq
MIRT2582623	hsa-miR-4782-5p	CLIP-seq
MIRT2582624	hsa-miR-4802-3p	CLIP-seq
MIRT2582625	hsa-miR-516b	CLIP-seq
MIRT2582626	hsa-miR-548a-5p	CLIP-seq
MIRT2582627	hsa-miR-548ab	CLIP-seq
MIRT2582628	hsa-miR-548ak	CLIP-seq
MIRT2582629	hsa-miR-548b-5p	CLIP-seq
MIRT2582630	hsa-miR-548c-5p	CLIP-seq
MIRT2582631	hsa-miR-548d-5p	CLIP-seq
MIRT2582632	hsa-miR-548h	CLIP-seq
MIRT2582633	hsa-miR-548i	CLIP-seq
MIRT2582634	hsa-miR-548j	CLIP-seq
MIRT2582635	hsa-miR-548k	CLIP-seq
MIRT2582636	hsa-miR-548l	CLIP-seq
MIRT2582637	hsa-miR-548n	CLIP-seq
MIRT2582638	hsa-miR-548w	CLIP-seq
MIRT2582639	hsa-miR-548y	CLIP-seq
MIRT2582640	hsa-miR-559	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0005515	Function	Protein binding	IPI	21516116, 25416956, 32296183
GO:0005576	Component	Extracellular region	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005615	Component	Extracellular space	IEA
GO:0005886	Component	Plasma membrane	IEA
GO:0008083	Function	Growth factor activity	IEA
GO:0016020	Component	Membrane	IEA
GO:0038138	Process	ERBB4-ERBB4 signaling pathway	IEA
GO:0048018	Function	Receptor ligand activity	IDA	23033483
GO:0048018	Function	Receptor ligand activity	IEA

Other IDs

• MIM: 610894
• HGNC: 29862
• e!Ensembl: ENSG00000169752

Protein

• UniProt ID: Q8WWG1
• Protein name: Pro-neuregulin-4, membrane-bound isoform (Pro-NRG4) [Cleaved into: Neuregulin-4 (NRG-4)]
• Protein function: Low affinity ligand for the ERBB4 tyrosine kinase receptor. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. Does not bind to the ERBB1, ERBB2 and E
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00008	EGF	9 → 44	EGF-like domain	Domain

• Sequence:

  MPTDHEEPCGPSHKSFCLNGGLCYVIPTIPSPFCRCVENYTGARCEEVFLPGSSIQTKSN
  LFEAFVALAVLVTLIIGAFYFLCRKGHFQRASSVQYDINLVETSSTSAHHSHEQH

• Sequence length: 115

Pathways

KEGG:

ErbB signaling pathway
Amyotrophic lateral sclerosis

Reactome:

Signaling by ERBB2
Signaling by ERBB4
SHC1 events in ERBB2 signaling
PI3K events in ERBB4 signaling
SHC1 events in ERBB4 signaling
PIP3 activates AKT signaling
GRB2 events in ERBB2 signaling
PI3K events in ERBB2 signaling
Constitutive Signaling by Aberrant PI3K in Cancer
RAF/MAP kinase cascade
ERBB2 Regulates Cell Motility
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
ERBB2 Activates PTK6 Signaling
Downregulation of ERBB2 signaling
Signaling by ERBB2 KD Mutants
Signaling by ERBB2 TMD/JMD mutants

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
GOUT	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Adenocarcinoma, Clear Cell	Adenocarcinoma	BEFREE	29633253		★☆☆☆☆ Found in Text Mining only
Arteriosclerosis	Arteriosclerosis	BEFREE	28918492		★☆☆☆☆ Found in Text Mining only
Arthritis, Gouty	Gouty arthritis	GWASDB_DG	23263486		★☆☆☆☆ Found in Text Mining only
Atherosclerosis	Atherosclerosis	BEFREE	28918492		★☆☆☆☆ Found in Text Mining only
Beta ketothiolase deficiency	Beta-ketothiolase deficiency	Pubtator	15583696	Inhibit	★☆☆☆☆ Found in Text Mining only
Bladder Neoplasm	Bladder Neoplasm	LHGDN	15583696		★☆☆☆☆ Found in Text Mining only
Carcinoma Renal Cell	Renal cell carcinoma	Pubtator	29633253	Associate	★☆☆☆☆ Found in Text Mining only
Cardiovascular Diseases	Cardiovascular Diseases	BEFREE	28918492		★☆☆☆☆ Found in Text Mining only
Chronic kidney disease stage 5	Kidney Disease	BEFREE	31153139		★☆☆☆☆ Found in Text Mining only
Chronic Kidney Diseases	Kidney Disease	BEFREE	31153139		★☆☆☆☆ Found in Text Mining only
Colitis	Colitis	BEFREE	23033483, 28230865		★☆☆☆☆ Found in Text Mining only
Cone-Rod Dystrophies	Cone-rod dystrophy	BEFREE	17174953		★☆☆☆☆ Found in Text Mining only
Cone-Rod Dystrophy 2	Cone-rod dystrophy	BEFREE	17174953		★☆☆☆☆ Found in Text Mining only
Coronary Arteriosclerosis	Coronary Arteriosclerosis	BEFREE	30393265		★☆☆☆☆ Found in Text Mining only
Coronary Artery Disease	Coronary artery disease	BEFREE	30393265		★☆☆☆☆ Found in Text Mining only
Coronary Disease	Coronary artery disease	Pubtator	36915073	Associate	★☆☆☆☆ Found in Text Mining only
Coronary heart disease	Coronary Heart Disease	BEFREE	30393265		★☆☆☆☆ Found in Text Mining only
Depressive disorder	Mental Depression	BEFREE	29317193		★☆☆☆☆ Found in Text Mining only
Diabetes	Diabetes	BEFREE	27862843, 31656034, 31815951		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus	Diabetes Mellitus	BEFREE	27862843, 31656034, 31815951		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus Type 2	Diabetes mellitus, type 2	Pubtator	36915073	Associate	★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus, Non-Insulin-Dependent	Diabetes Mellitus	BEFREE	25401691, 28752050, 28918492, 29721105, 30322810, 30528184, 30935234, 31153139, 31632525, 31656034		★☆☆☆☆ Found in Text Mining only
Diabetic Nephropathy	Diabetic Nephropathy	BEFREE	31153139, 31632525		★☆☆☆☆ Found in Text Mining only
Dyslipidemias	Dyslipidemias	BEFREE	29721105		★☆☆☆☆ Found in Text Mining only
Fatty Liver	Fatty Liver	BEFREE	25401691, 28709749, 30935234		★☆☆☆☆ Found in Text Mining only
Fatty Liver	Fatty liver	Pubtator	39735994	Inhibit	★☆☆☆☆ Found in Text Mining only
Fatty Liver Alcoholic	Fatty liver, alcoholic	Pubtator	39735994	Inhibit	★☆☆☆☆ Found in Text Mining only
Fatty Liver Disease	Fatty Liver	BEFREE	29106384		★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	Pubtator	34054873	Associate	★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	34054873	Associate	★☆☆☆☆ Found in Text Mining only
Gout	Gout	GWASDB_DG	23263486		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hyperglycemia	Hyperglycemia	BEFREE	30322810		★☆☆☆☆ Found in Text Mining only
Hypertension	Hypertension	Pubtator	36915073	Associate	★☆☆☆☆ Found in Text Mining only
Hyperthyroidism	Hyperthyroidism	BEFREE	31063974		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory Bowel Disease	BEFREE	23033483		★☆☆☆☆ Found in Text Mining only
Insulin Resistance	Diabetes mellitus, type 2	Pubtator	31064233	Associate	★☆☆☆☆ Found in Text Mining only
Kidney Failure, Chronic	Kidney Failure	BEFREE	31153139		★☆☆☆☆ Found in Text Mining only
LATE-ONSET RETINAL DEGENERATION (disorder)	RETINAL DEGENERATION	BEFREE	17174953		★☆☆☆☆ Found in Text Mining only
Lymphoma	Lymphoma	BEFREE	21805036		★☆☆☆☆ Found in Text Mining only
Lymphoma, Follicular	Lymphoma	BEFREE	21805036		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	15141382		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	BEFREE	17545517, 20959441		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of stomach	Stomach Neoplasms	BEFREE	24728052		★☆☆☆☆ Found in Text Mining only
Melanoma	Melanoma	Pubtator	24709886	Associate	★☆☆☆☆ Found in Text Mining only
Mental Depression	Mental Depression	BEFREE	29317193		★☆☆☆☆ Found in Text Mining only
Metabolic Diseases	Metabolic Diseases	BEFREE	28752050, 29902456, 30393265, 30935234		★☆☆☆☆ Found in Text Mining only
Metabolic Syndrome X	Metabolic Syndrome	BEFREE	27772531, 29721105		★☆☆☆☆ Found in Text Mining only
Mucosa-Associated Lymphoid Tissue Lymphoma	Mucosa-associated lymphoma	BEFREE	21805036		★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	16469638, 24728052		★☆☆☆☆ Found in Text Mining only
nervous system disorder	Nervous System Disorder	BEFREE	29317193		★☆☆☆☆ Found in Text Mining only
Non-alcoholic Fatty Liver Disease	Non-Alcoholic Fatty Liver Disease	BEFREE	25401691, 28752050, 31063974, 31632525		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	BEFREE	25401691, 28752050, 29721105, 29902456, 30322810, 31063974, 31782243		★☆☆☆☆ Found in Text Mining only
Peripheral Nervous System Diseases	Nervous System Diseases	BEFREE	30322810		★☆☆☆☆ Found in Text Mining only
Peripheral Neuropathy	Peripheral Neuropathy	BEFREE	30322810		★☆☆☆☆ Found in Text Mining only
Polycystic Ovary Syndrome	Polycystic ovary syndrome	Pubtator	31064233	Stimulate	★☆☆☆☆ Found in Text Mining only
Prostate carcinoma	Prostate cancer	BEFREE	17545517, 20959441		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic Neoplasms	BEFREE	17545517		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic Neoplasms	LHGDN	17545517		★☆☆☆☆ Found in Text Mining only
Retinal Diseases	Retinal Diseases	BEFREE	11006213		★☆☆☆☆ Found in Text Mining only
Retinitis Pigmentosa	Retinitis Pigmentosa	BEFREE	30945270		★☆☆☆☆ Found in Text Mining only
Rod-Cone Dystrophy	Rod-cone dystrophy	BEFREE	17174953		★☆☆☆☆ Found in Text Mining only
Schizophrenia	Schizophrenia	BEFREE	29317193		★☆☆☆☆ Found in Text Mining only
Steatohepatitis	Fatty Liver	BEFREE	25401691, 28709749, 29106384, 30935234		★☆☆☆☆ Found in Text Mining only
Stomach Carcinoma	Stomach Carcinoma	BEFREE	24728052		★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	24728052	Associate	★☆☆☆☆ Found in Text Mining only
Truncus Arteriosus, Persistent	Persistent truncus arteriosus	BEFREE	16469638		★☆☆☆☆ Found in Text Mining only
Urinary Bladder Neoplasms	Urinary bladder neoplasms	Pubtator	15583696	Associate	★☆☆☆☆ Found in Text Mining only