V-Erb A Erythroblastic Leukemia Viral Oncogene Homolog 4 (ErbB4)

HER4; P180erbB4; Receptor Tyrosine-Protein Kinase ErbB-4; Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4

SPN	U656
HGNC	3432
MGI	104771
PubMed	22076439
RGD	620486
UniProt	Q15303
Wiki	ERBB4

ErbB-4 is a member of the epidermal growth factor receptor subfamily. ERBB4 is a single-pass type I transmembrane protein with multiple furin-like cysteine rich domains, 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-2 and -3, heparin-binding EGF-like growth factor and betacellulin. Ligand binding 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.

Reference

"Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family."
Proc. Natl. Acad. Sci. U.S.A. 90:1746-1750(1993) [PubMed] [Europe PMC] [Abstract]

"A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester."
J. Biol. Chem. 272:26761-26768(1997) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor."
J. Biol. Chem. 268:18407-18410(1993) [PubMed] [Europe PMC] [Abstract]

"Heregulin induces tyrosine phosphorylation of HER4/p180erbB4."
Nature 366:473-475(1993) [PubMed] [Europe PMC] [Abstract]

"HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers."
J. Biol. Chem. 271:4813-4818(1996) [PubMed] [Europe PMC] [Abstract]

"Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta."
Oncogene 12:345-353(1996) [PubMed] [Europe PMC] [Abstract]

"Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation."
EMBO J. 16:1268-1278(1997) [PubMed] [Europe PMC] [Abstract]

"Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases."
Nature 387:512-516(1997) [PubMed] [Europe PMC] [Abstract]

"Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4."
Oncogene 15:2841-2848(1997) [PubMed] [Europe PMC] [Abstract]

"Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4."
Proc. Natl. Acad. Sci. U.S.A. 94:9562-9567(1997) [PubMed] [Europe PMC] [Abstract]

"Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3."
J. Biol. Chem. 273:7717-7724(1998) [PubMed] [Europe PMC] [Abstract]

"ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases."
J. Biol. Chem. 274:17209-17218(1999) [PubMed] [Europe PMC] [Abstract]

"Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase."
Oncogene 18:2607-2615(1999) [PubMed] [Europe PMC] [Abstract]

"Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase."
Oncogene 18:2681-2689(1999) [PubMed] [Europe PMC] [Abstract]

"A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis."
J. Biol. Chem. 275:8641-8649(2000) [PubMed] [Europe PMC] [Abstract]

"Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4."
J. Biol. Chem. 275:10379-10387(2000) [PubMed] [Europe PMC] [Abstract]

"Ligand discrimination in signaling through an ErbB4 receptor homodimer."
J. Biol. Chem. 275:19803-19807(2000) [PubMed] [Europe PMC] [Abstract]

"The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses."
Proc. Natl. Acad. Sci. U.S.A. 97:3596-3601(2000) [PubMed] [Europe PMC] [Abstract]

"BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells."
Biochem. Biophys. Res. Commun. 281:25-31(2001) [PubMed] [Europe PMC] [Abstract]

"Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells."
Mol. Cell. Biol. 21:4265-4275(2001) [PubMed] [Europe PMC] [Abstract]

"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. 278:33334-33341(2003) [PubMed] [Europe PMC] [Abstract]

"Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein."
Mol. Cancer Res. 1:765-775(2003) [PubMed] [Europe PMC] [Abstract]

"The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone."
J. Cell Biol. 167:469-478(2004) [PubMed] [Europe PMC] [Abstract]

"WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function."
Cancer Res. 65:6764-6772(2005) [PubMed] [Europe PMC] [Abstract]

"Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities."
J. Biol. Chem. 280:19777-19783(2005) [PubMed] [Europe PMC] [Abstract]

"The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells."
Cancer Res. 66:6412-6420(2006) [PubMed] [Europe PMC] [Abstract]

"ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression."
J. Biol. Chem. 281:25373-25380(2006) [PubMed] [Europe PMC] [Abstract]

"Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth."
Mol. Biol. Cell 17:67-79(2006) [PubMed] [Europe PMC] [Abstract]

"The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells."
Mol. Biol. Cell 17:4118-4129(2006) [PubMed] [Europe PMC] [Abstract]

"Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines."
Oncol. Res. 16:179-193(2006) [PubMed] [Europe PMC] [Abstract]

"HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4."
Cancer Res. 67:6582-6590(2007) [PubMed] [Europe PMC] [Abstract]

"Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners."
Cell. Signal. 19:466-471(2007) [PubMed] [Europe PMC] [Abstract]

"Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains."
Oncogene 26:6905-6914(2007) [PubMed] [Europe PMC] [Abstract]

"System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties."
Chem. Biol. 15:808-817(2008) [PubMed] [Europe PMC] [Abstract]

"Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells."
FASEB J. 23:1935-1945(2009) [PubMed] [Europe PMC] [Abstract]

"Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer."
J. Biol. Chem. 284:5582-5591(2009) [PubMed] [Europe PMC] [Abstract]

"WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer."
Oncogene 28:2948-2958(2009) [PubMed] [Europe PMC] [Abstract]

"Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways."
Mol. Cancer Res. 8:1388-1398(2010) [PubMed] [Europe PMC] [Abstract]

"Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines."
Exp. Cell Res. 317:1476-1489(2011) [PubMed] [Europe PMC] [Abstract]

"ErbB4 signaling during breast and neural development: novel genetic models reveal unique ErbB4 activities."
Cell Cycle 2:555-559(2003) [PubMed] [Europe PMC] [Abstract]

"The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches."
Histol. Histopathol. 20:1005-1015(2005) [PubMed] [Europe PMC] [Abstract]

"ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition."
J. Mammary Gland Biol. Neoplasia 13:235-246(2008) [PubMed] [Europe PMC] [Abstract]

"HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer."
J. Mammary Gland Biol. Neoplasia 13:247-258(2008) [PubMed] [Europe PMC] [Abstract]

"Role of ErbB4 in breast cancer."
J. Mammary Gland Biol. Neoplasia 13:259-268(2008) [PubMed] [Europe PMC] [Abstract]

"Neuregulin-1/ErbB signaling and chronic heart failure."
Adv. Pharmacol. 59:31-51(2010) [PubMed] [Europe PMC] [Abstract]

"Function of ERBB4 is determined by alternative splicing."
Cell Cycle 10:2647-2657(2011) [PubMed] [Europe PMC] [Abstract]

"The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand."
Proc. Natl. Acad. Sci. U.S.A. 102:15024-15029(2005) [PubMed] [Europe PMC] [Abstract]

"6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases."
Proc. Natl. Acad. Sci. U.S.A. 105:2773-2778(2008) [PubMed] [Europe PMC] [Abstract]

"Mechanism of activation and inhibition of the HER4/ErbB4 kinase."
Structure 16:460-467(2008) [PubMed] [Europe PMC] [Abstract]

"Patterns of somatic mutation in human cancer genomes."
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]

"ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19."
Am. J. Hum. Genet. 93:900-905(2013) [PubMed] [Europe PMC] [Abstract]