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Identification
HMDB Protein ID HMDBP01376
Secondary Accession Numbers
  • 6672
Name Receptor tyrosine-protein kinase erbB-4
Synonyms
  1. 4ICD
  2. E4ICD
  3. ERBB4 intracellular domain
  4. Proto-oncogene-like protein c-ErbB-4
  5. Tyrosine kinase-type cell surface receptor HER4
  6. p180erbB4
  7. s80HER4
Gene Name ERBB4
Protein Type Enzyme
Biological Properties
General Function Involved in transmembrane receptor protein tyrosine kinase activity
Specific Function Specifically binds and is activated by neuregulins, NRG- 2, NRG-3, heparin-binding EGF-like growth factor, betacellulin and NTAK. Interaction with these factors induces cell differentiation. Not activated by EGF, TGF-A, and amphiregulin. The C-terminal fragment (CTF) of isoform JMA-A CYT-2 (containing E4ICD2) can stimulate transcription in the presence of YAP1. ERBB4 intracellular domain is involved in the regulation of cell growth. Conflicting reports are likely due at least in part to the opposing effects of the isoform-specific and nuclear-translocated ERBB4 intracellular domains (E4ICD1 and E4ICD2). Overexpression studies in epithelium show growth inhibition using E4ICD1 and increased proliferation using E4ICD2. E4ICD2 has greater in vitro kinase activity than E4ICD1. The kinase activity is required for the nuclear translocation of E4ICD2
Pathways Not Available
Reactions Not Available
GO Classification
Component
membrane
cell part
membrane part
intrinsic to membrane
integral to membrane
Function
protein tyrosine kinase activity
transmembrane receptor protein tyrosine kinase activity
binding
catalytic activity
transferase activity
transferase activity, transferring phosphorus-containing groups
kinase activity
nucleoside binding
purine nucleoside binding
adenyl nucleotide binding
adenyl ribonucleotide binding
atp binding
receptor signaling protein tyrosine kinase activity
protein binding
protein kinase activity
Process
phosphorus metabolic process
phosphate metabolic process
peptidyl-tyrosine phosphorylation
enzyme linked receptor protein signaling pathway
transmembrane receptor protein tyrosine kinase signaling pathway
metabolic process
cellular metabolic process
protein amino acid phosphorylation
signaling
signaling pathway
cell surface receptor linked signaling pathway
phosphorylation
Cellular Location
  1. ERBB4 intracellular domain:Nucleus
Gene Properties
Chromosome Location Chromosome:2
Locus 2q33.3-q34
SNPs ERBB4
Gene Sequence
>3927 bp
ATGAAGCCGGCGACAGGACTTTGGGTCTGGGTGAGCCTTCTCGTGGCGGCGGGGACCGTC
CAGCCCAGCGATTCTCAGTCAGTGTGTGCAGGAACGGAGAATAAACTGAGCTCTCTCTCT
GACCTGGAACAGCAGTACCGAGCCTTGCGCAAGTACTATGAAAACTGTGAGGTTGTCATG
GGCAACCTGGAGATAACCAGCATTGAGCACAACCGGGACCTCTCCTTCCTGCGGTCTGTT
CGAGAAGTCACAGGCTACGTGTTAGTGGCTCTTAATCAGTTTCGTTACCTGCCTCTGGAG
AATTTACGCATTATTCGTGGGACAAAACTTTATGAGGATCGATATGCCTTGGCAATATTT
TTAAACTACAGAAAAGATGGAAACTTTGGACTTCAAGAACTTGGATTAAAGAACTTGACA
GAAATCCTAAATGGTGGAGTCTATGTAGACCAGAACAAATTCCTTTGTTATGCAGACACC
ATTCATTGGCAAGATATTGTTCGGAACCCATGGCCTTCCAACTTGACTCTTGTGTCAACA
AATGGTAGTTCAGGATGTGGACGTTGCCATAAGTCCTGTACTGGCCGTTGCTGGGGACCC
ACAGAAAATCATTGCCAGACTTTGACAAGGACGGTGTGTGCAGAACAATGTGACGGCAGA
TGCTACGGACCTTACGTCAGTGACTGCTGCCATCGAGAATGTGCTGGAGGCTGCTCAGGA
CCTAAGGACACAGACTGCTTTGCCTGCATGAATTTCAATGACAGTGGAGCATGTGTTACT
CAGTGTCCCCAAACCTTTGTCTACAATCCAACCACCTTTCAACTGGAGCACAATTTCAAT
GCAAAGTACACATATGGAGCATTCTGTGTCAAGAAATGTCCACATAACTTTGTGGTAGAT
TCCAGTTCTTGTGTGCGTGCCTGCCCTAGTTCCAAGATGGAAGTAGAAGAAAATGGGATT
AAAATGTGTAAACCTTGCACTGACATTTGCCCAAAAGCTTGTGATGGCATTGGCACAGGA
TCATTGATGTCAGCTCAGACTGTGGATTCCAGTAACATTGACAAATTCATAAACTGTACC
AAGATCAATGGGAATTTGATCTTTCTAGTCACTGGTATTCATGGGGACCCTTACAATGCA
ATTGAAGCCATAGACCCAGAGAAACTGAACGTCTTTCGGACAGTCAGAGAGATAACAGGT
TTCCTGAACATACAGTCATGGCCACCAAACATGACTGACTTCAGTGTTTTTTCTAACCTG
GTGACCATTGGTGGAAGAGTACTCTATAGTGGCCTGTCCTTGCTTATCCTCAAGCAACAG
GGCATCACCTCTCTACAGTTCCAGTCCCTGAAGGAAATCAGCGCAGGAAACATCTATATT
ACTGACAACAGCAACCTGTGTTATTATCATACCATTAACTGGACAACACTCTTCAGCACA
ATCAACCAGAGAATAGTAATCCGGGACAACAGAAAAGCTGAAAATTGTACTGCTGAAGGA
ATGGTGTGCAACCATCTGTGTTCCAGTGATGGCTGTTGGGGACCTGGGCCAGACCAATGT
CTGTCGTGTCGCCGCTTCAGTAGAGGAAGGATCTGCATAGAGTCTTGTAACCTCTATGAT
GGTGAATTTCGGGAGTTTGAGAATGGCTCCATCTGTGTGGAGTGTGACCCCCAGTGTGAG
AAGATGGAAGATGGCCTCCTCACATGCCATGGACCGGGTCCTGACAACTGTACAAAGTGC
TCTCATTTTAAAGATGGCCCAAACTGTGTGGAAAAATGTCCAGATGGCTTACAGGGGGCA
AACAGTTTCATTTTCAAGTATGCTGATCCAGATCGGGAGTGCCACCCATGCCATCCAAAC
TGCACCCAAGGGTGTAACGGTCCCACTAGTCATGACTGCATTTACTACCCATGGACGGGC
CATTCCACTTTACCACAACATGCTAGAACTCCCCTGATTGCAGCTGGAGTAATTGGTGGG
CTCTTCATTCTGGTCATTGTGGGTCTGACATTTGCTGTTTATGTTAGAAGGAAGAGCATC
AAAAAGAAAAGAGCCTTGAGAAGATTCTTGGAAACAGAGTTGGTGGAACCATTAACTCCC
AGTGGCACAGCACCCAATCAAGCTCAACTTCGTATTTTGAAAGAAACTGAGCTGAAGAGG
GTAAAAGTCCTTGGCTCAGGTGCTTTTGGAACGGTTTATAAAGGTATTTGGGTACCTGAA
GGAGAAACTGTGAAGATTCCTGTGGCTATTAAGATTCTTAATGAGACAACTGGTCCCAAG
GCAAATGTGGAGTTCATGGATGAAGCTCTGATCATGGCAAGTATGGATCATCCACACCTA
GTCCGGTTGCTGGGTGTGTGTCTGAGCCCAACCATCCAGCTGGTTACTCAACTTATGCCC
CATGGCTGCCTGTTGGAGTATGTCCACGAGCACAAGGATAACATTGGATCACAACTGCTG
CTTAACTGGTGTGTCCAGATAGCTAAGGGAATGATGTACCTGGAAGAAAGACGACTCGTT
CATCGGGATTTGGCAGCCCGTAATGTCTTAGTGAAATCTCCAAACCATGTGAAAATCACA
GATTTTGGGCTAGCCAGACTCTTGGAAGGAGATGAAAAAGAGTACAATGCTGATGGAGGA
AAGATGCCAATTAAATGGATGGCTCTGGAGTGTATACATTACAGGAAATTCACCCATCAG
AGTGACGTTTGGAGCTATGGAGTTACTATATGGGAACTGATGACCTTTGGAGGAAAACCC
TATGATGGAATTCCAACGCGAGAAATCCCTGATTTATTAGAGAAAGGAGAACGTTTGCCT
CAGCCTCCCATCTGCACTATTGACGTTTACATGGTCATGGTCAAATGTTGGATGATTGAT
GCTGACAGTAGACCTAAATTTAAGGAACTGGCTGCTGAGTTTTCAAGGATGGCTCGAGAC
CCTCAAAGATACCTAGTTATTCAGGGTGATGATCGTATGAAGCTTCCCAGTCCAAATGAC
AGCAAGTTCTTTCAGAATCTCTTGGATGAAGAGGATTTGGAAGATATGATGGATGCTGAG
GAGTACTTGGTCCCTCAGGCTTTCAACATCCCACCTCCCATCTATACTTCCAGAGCAAGA
ATTGACTCGAATAGGAGTGAAATTGGACACAGCCCTCCTCCTGCCTACACCCCCATGTCA
GGAAACCAGTTTGTATACCGAGATGGAGGTTTTGCTGCTGAACAAGGAGTGTCTGTGCCC
TACAGAGCCCCAACTAGCACAATTCCAGAAGCTCCTGTGGCACAGGGTGCTACTGCTGAG
ATTTTTGATGACTCCTGCTGTAATGGCACCCTACGCAAGCCAGTGGCACCCCATGTCCAA
GAGGACAGTAGCACCCAGAGGTACAGTGCTGACCCCACCGTGTTTGCCCCAGAACGGAGC
CCACGAGGAGAGCTGGATGAGGAAGGTTACATGACTCCTATGCGAGACAAACCCAAACAA
GAATACCTGAATCCAGTGGAGGAGAACCCTTTTGTTTCTCGGAGAAAAAATGGAGACCTT
CAAGCATTGGATAATCCCGAATATCACAATGCATCCAATGGTCCACCCAAGGCCGAGGAT
GAGTATGTGAATGAGCCACTGTACCTCAACACCTTTGCCAACACCTTGGGAAAAGCTGAG
TACCTGAAGAACAACATACTGTCAATGCCAGAGAAGGCCAAGAAAGCGTTTGACAACCCT
GACTACTGGAACCACAGCCTGCCACCTCGGAGCACCCTTCAGCACCCAGACTACCTGCAG
GAGTACAGCACAAAATATTTTTATAAACAGAATGGGCGGATCCGGCCTATTGTGGCAGAG
AATCCTGAATACCTCTCTGAGTTCTCCCTGAAGCCAGGCACTGTGCTGCCGCCTCCACCT
TACAGACACCGGAATACTGTGGTGTAA
Protein Properties
Number of Residues 1308
Molecular Weight 146806.9
Theoretical pI 6.35
Pfam Domain Function
Signals
  • 1-25
Transmembrane Regions
  • 652-675
Protein Sequence
>Receptor tyrosine-protein kinase erbB-4
MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF
LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST
NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG
PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD
SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT
KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL
VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST
INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD
GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA
NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG
LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR
VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL
VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV
HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ
SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID
ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE
EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP
YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS
PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED
EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ
EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
GenBank ID Protein 4885215
UniProtKB/Swiss-Prot ID Q15303
UniProtKB/Swiss-Prot Entry Name ERBB4_HUMAN
PDB IDs Not Available
GenBank Gene ID NM_005235.2
GeneCard ID ERBB4
GenAtlas ID ERBB4
HGNC ID HGNC:3432
References
General References
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  3. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. [PubMed:17344846 ]
  4. Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D: Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. Mol Cancer Res. 2003 Aug;1(10):765-75. [PubMed:12939402 ]
  5. Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M: Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50. [PubMed:8383326 ]
  6. Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M: A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem. 1997 Oct 17;272(42):26761-8. [PubMed:9334263 ]
  7. Rio C, Buxbaum JD, Peschon JJ, Corfas G: Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4. J Biol Chem. 2000 Apr 7;275(14):10379-87. [PubMed:10744726 ]
  8. Garcia RA, Vasudevan K, Buonanno A: The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3596-601. [PubMed:10725395 ]
  9. Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B, Earp HS 3rd: Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001 Jul;21(13):4265-75. [PubMed:11390655 ]
  10. Komuro A, Nagai M, Navin NE, Sudol M: WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003 Aug 29;278(35):33334-41. Epub 2003 Jun 13. [PubMed:12807903 ]
  11. Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM: WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res. 2005 Aug 1;65(15):6764-72. [PubMed:16061658 ]
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  13. Linggi B, Carpenter G: ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression. J Biol Chem. 2006 Sep 1;281(35):25373-80. Epub 2006 Jun 30. [PubMed:16815842 ]
  14. Maatta JA, Sundvall M, Junttila TT, Peri L, Laine VJ, Isola J, Egeblad M, Elenius K: Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth. Mol Biol Cell. 2006 Jan;17(1):67-79. Epub 2005 Oct 26. [PubMed:16251361 ]
  15. Strunk KE, Husted C, Miraglia LC, Sandahl M, Rearick WA, Hunter DM, Earp HS 3rd, Muraoka-Cook RS: HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4. Cancer Res. 2007 Jul 15;67(14):6582-90. [PubMed:17638867 ]
  16. Sundvall M, Peri L, Maatta JA, Tvorogov D, Paatero I, Savisalo M, Silvennoinen O, Yarden Y, Elenius K: Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains. Oncogene. 2007 Oct 18;26(48):6905-14. Epub 2007 May 7. [PubMed:17486069 ]
  17. Zeng F, Xu J, Harris RC: Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells. FASEB J. 2009 Jun;23(6):1935-45. doi: 10.1096/fj.08-121947. Epub 2009 Feb 4. [PubMed:19193720 ]
  18. Li Y, Zhou Z, Alimandi M, Chen C: WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer. Oncogene. 2009 Aug 20;28(33):2948-58. doi: 10.1038/onc.2009.162. Epub 2009 Jun 29. [PubMed:19561640 ]
  19. Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ: The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15024-9. Epub 2005 Oct 3. [PubMed:16203964 ]