ERBB4
entrez
2066
canonical
uniprot
Q15303
canonical
ensembl
ENSG00000178568
resolver
ensp
ENSP00000260943
resolver
ensp
ENSP00000342235
resolver
ensp
ENSP00000403204
resolver
genesymbol
ERBB4
resolver
genesymbol_syn
HER4
resolver
hgnc
HGNC:3432
resolver
uniprot
B7ZLD7
resolver
uniprot
B7ZLE2
resolver
uniprot
B7ZLE3
resolver
uniprot
Q2M1W1
resolver
uniprot
Q59EW4
resolver
uniprot_entry
ERBB4_HUMAN
resolver
uniprot_sec
B7ZLD7
resolver
uniprot_sec
B7ZLE2
resolver
uniprot_sec
B7ZLE3
resolver
uniprot_sec
Q2M1W1
resolver
uniprot_sec
Q59EW4
resolver
activity_regulation
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. {ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:18334220, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:21439954, ECO:0000269|PubMed:8617750}.
uniprot
proteins
amino_acid_sequence
MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVMGNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIFLNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVSTNGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVDSSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCTKINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNLVTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFSTINQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYDGEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGANSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGGLFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQSDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVPYRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQEYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
uniprot
proteins
disease_involvement
DISEASE: 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. {ECO:0000269|PubMed:24119685}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.10.1
uniprot
proteins
function
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. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}.
uniprot
proteins
mass_dalton
146808
uniprot
proteins
mutagenesis
MUTAGEN 646; /note="Q->C: Constitutively activated kinase."; /evidence="ECO:0000269|PubMed:17120616"; MUTAGEN 675; /note="V->A: Abolishes proteolytic processing and nuclear localization."; /evidence="ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:17638867"; MUTAGEN 681..684; /note="KKKR->EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain."; /evidence="ECO:0000269|PubMed:15534001"; MUTAGEN 710; /note="L->N: Strongly reduced autophosphorylation."; /evidence="ECO:0000269|PubMed:18287036"; MUTAGEN 721; /note="V->I: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 751; /note="K->R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization."; /evidence="ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867"; MUTAGEN 766; /note="M->R: Strongly reduced autophosphorylation."; /evidence="ECO:0000269|PubMed:18287036"; MUTAGEN 773; /note="A->S: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 782; /note="R->Q: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 810; /note="E->K: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 843; /note="D->N: Loss of kinase activity."; /evidence="ECO:0000269|PubMed:16978839"; MUTAGEN 854; /note="P->Q: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 861; /note="D->Y: Loss of kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 864; /note="L->R: Strongly reduced autophosphorylation."; /evidence="ECO:0000269|PubMed:18287036"; MUTAGEN 872; /note="E->K: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 926; /note="T->M: No effect on kinase activity."; /evidence="ECO:0000269|PubMed:19098003"; MUTAGEN 947; /note="I->R: Constitutively autophosphorylated."; /evidence="ECO:0000269|PubMed:18287036"; MUTAGEN 992; /note="R->A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000."; /evidence="ECO:0000269|PubMed:17638867"; MUTAGEN 995; /note="L->A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000."; /evidence="ECO:0000269|PubMed:17638867"; MUTAGEN 1000; /note="D->A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995."; /evidence="ECO:0000269|PubMed:17638867"; MUTAGEN 1035; /note="Y->A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301."; /evidence="ECO:0000269|PubMed:16061658"; MUTAGEN 1056; /note="Y->A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1."; /evidence="ECO:0000269|PubMed:19561640"; MUTAGEN 1056; /note="Y->F: Abolishes interaction with WWP1; when associated with F-1301."; /evidence="ECO:0000269|PubMed:19561640"; MUTAGEN 1301; /note="Y->A: Abolishes interaction with NEDD4 and impairs ubiquitination."; /evidence="ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640"; MUTAGEN 1301; /note="Y->A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1035. Loss of interaction with YAP1 and stimulation of transcription."; /evidence="ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640"; MUTAGEN 1301; /note="Y->F: Abolishes interaction with WWP1; when associated with F-1056."; /evidence="ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640
uniprot
proteins
post_translational_modification
PTM: 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. {ECO:0000269|PubMed:10744726, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:9334263}.; PTM: 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. {ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:17120616, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:18721752, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9168115}.; PTM: 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. {ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19193720}.
uniprot
proteins
protein_family
EGF receptor subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
Tyr protein kinase family
uniprot
proteins
pubmed
10348342
uniprot
proteins
pubmed
10353604
uniprot
proteins
pubmed
10358079
uniprot
proteins
pubmed
10722704
uniprot
proteins
pubmed
10725395
uniprot
proteins
pubmed
10744726
uniprot
proteins
pubmed
10867024
uniprot
proteins
pubmed
11178955
uniprot
proteins
pubmed
11390655
uniprot
proteins
pubmed
12807903
uniprot
proteins
pubmed
12939402
uniprot
proteins
pubmed
14504474
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15534001
uniprot
proteins
pubmed
15746097
uniprot
proteins
pubmed
15944951
uniprot
proteins
pubmed
16061658
uniprot
proteins
pubmed
16203964
uniprot
proteins
pubmed
16251361
uniprot
proteins
pubmed
16778220
uniprot
proteins
pubmed
16815842
uniprot
proteins
pubmed
16837552
uniprot
proteins
pubmed
16978839
uniprot
proteins
pubmed
17120616
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17486069
uniprot
proteins
pubmed
17638867
uniprot
proteins
pubmed
18287036
uniprot
proteins
pubmed
18334220
uniprot
proteins
pubmed
18437540
uniprot
proteins
pubmed
18454307
uniprot
proteins
pubmed
18473151
uniprot
proteins
pubmed
18721752
uniprot
proteins
pubmed
19098003
uniprot
proteins
pubmed
19193720
uniprot
proteins
pubmed
19561640
uniprot
proteins
pubmed
20858735
uniprot
proteins
pubmed
20933198
uniprot
proteins
pubmed
21439954
uniprot
proteins
pubmed
21811097
uniprot
proteins
pubmed
24119685
uniprot
proteins
pubmed
7689552
uniprot
proteins
pubmed
7902537
uniprot
proteins
pubmed
8383326
uniprot
proteins
pubmed
8570211
uniprot
proteins
pubmed
8617750
uniprot
proteins
pubmed
9135143
uniprot
proteins
pubmed
9168115
uniprot
proteins
pubmed
9275162
uniprot
proteins
pubmed
9334263
uniprot
proteins
pubmed
9419975
uniprot
proteins
pubmed
9516479
uniprot
proteins
sequence_length
1308
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19193720, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}; Single-pass type I membrane protein {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19193720, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}. Note=In response to NRG1 treatment, the activated receptor is internalized.; SUBCELLULAR LOCATION: [ERBB4 intracellular domain]: Nucleus {ECO:0000269|PubMed:17486069}. Mitochondrion {ECO:0000269|PubMed:17486069}. Note=Following proteolytical processing E4ICD (E4ICD1 or E4ICD2 generated from the respective isoforms) is translocated to the nucleus. Significantly more E4ICD2 than E4ICD1 is found in the nucleus. E4ICD2 colocalizes with YAP1 in the nucleus.
uniprot
proteins
transmembrane_region
TRANSMEM 652..675; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins