Signaling by ERBB4 (Homo sapiens)

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3, 7, 8, 10-12, 14...20, 2334, 74437, 8, 17, 31, 39...314432861, 7121, 25, 6154, 624361, 713122374774334, 74, 7560, 61, 69121254, 6254, 62124321, 60, 6932712, 34, 744, 54, 62314mitochondrial matrixcytosolnucleoplasmERBB4jmAcyt2s80 p-ERBB4cyt1homodimersERBB4 JM-A CYT-2 isoform NEDD4 UBA52(1-76) EGFR ERBB4jmAcyt1s80 S100B gene UBB(1-76) PIP3 activates AKTsignalingZn2+ ERBB4_ECDERBB4jmAcyt1m80 UBC(229-304) YAP1UBC(533-608) ERBB4s80:TAB2:NCOR1WWOXERBB4 JM-A CYT-2 isoform TAB2 PIK3CA ERBB4jmAcyt1ECD ERBB4s80:ESR1:estrogenWWP1 ERBB4jmAcyt1s80 CXCL12 geneADAM17 ESR1 ERBB4jmAcyt1s80 UBC(533-608) UBC(609-684) p21 RAS:GTPTAB2:NCOR1ERBB4jmAcyt2s80 p-ERBB4 homodimersUBC(1-76) ERBB4jmAcyt2s80 ERBB4s80:WWOXERBB4m80 SOS1 ATPSHC1WWP1 p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform Activation of NMDAreceptors andpostsynaptic eventsERBB4jmAcyt1s80 EGF-like ligands ERBB4 JM-A CYT-1 isoform PSEN1(299-467) ADPERBB4jmAcyt2s80 ESTG PI(4,5)P2ERBB4s80:ESR1:estrogen:PGR geneKRAS PGR geneTAB2 UBC(1-76) UBC(153-228) ERBB4s80:ESR1:estrogen:CXCL12 geneERBB3-1 p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform ERBB4jmAcyt1s80 ERBB4 p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform SOS1 ERBB4 JM-A CYT-2 isoform ERBB4jmAcyt1s80 ERBB4jmAcyt1s80 p-ERBB4cyt1 homodimers UBA52(1-76) PI(3,4,5)P3UBA52(1-76) ERBB3-1 NRG1 Neuregulins NCOR1 GFAP geneADAM17GTPGRB2-1:SOS1ERBB4s80:MyrG-p-Y419-SRCEGF-like ligands p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform ERBB4s80:YAP1SHC1:p-ERBB4EGF-like ligands UBC(305-380) ERBB4 CYT-1 isoforms ESR1 UBC(381-456) UBB(1-76) ERBB4jmAcyt1s80 NEDD4 CXCL12 gene ERBB4jmAcyt2ECD UBC(533-608) EGF:EGFRGRB2:SOS1:p-Y349,350-SHC1:p-ERBB4ERBB4jmAcyt2s80 Neuregulins ESR1 ERBB4jmAcyt1s80 ERBB4jmAcyt1s80 ESR1 ERBB4jmAcyt2s80 ERBB4s80 YAP1 PIK3R1 ERBB4jmAcyt1s80 ERBB4/m80/s80:WWP1/ITCHERBB4:ERBB3heterodimerp-Y694-STAT5A ERBB4s80:TAB2:NCOR1GTP NRGs/EGF-likeligands:ERBB4UBB(77-152) NRG1/2:ERBB3UBB(77-152) EGF-like ligands ERBB4s80 UBB(153-228) ESTG WWP1 p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ERBB4s80 ERBB4jmAcyt2s80 ITCH ERBB4s80CSN2 gene ERBB4jmAcyt1s80 NRG2 TAB2 EGF-like ligands ERBB4m80 p-ERBB4 JM-AhomodimersERBB4jmAcyt2s80 p-Y694-STAT5A ERBB4 JM-A CYT-2 isoform SHC1 UBC(77-152) ERBB4 JM-A CYT-2 isoform Neuregulins p-Y694-STAT5A ERBB4jmAcyt1s80 ATPUBC(77-152) ERBB4cyt1 homodimers ERBB4jmAcyt1s80 UBC(457-532) EGF-like ligands EGF-like ligands Neuregulins GDP UBC(457-532) Ub-ERBB4:WWP1/ITCHNeuregulins Neuregulins p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform ERBB4s80:p-Y694-STAT5AMyrG-p-Y419-SRC ERBB4/ERBB4m80/ERBB4s80EGF-like ligands ERBB4 JM-B CYT-1 isoform NRGs/EGF-likeligandsS100BUBC(381-456) ERBB4jmAcyt1s80:NEDD4YAP1- and WWTR1(TAZ)-stimulatedgene expressionPSEN2(298-448) ERBB4 HRAS UBC(153-228) GFAPERBB4jmAcyt2s80 GFAP gene ERBB4 ERBB4 JM-A CYT-1 isoform UBC(153-228) ERBB4jmAcyt2s80 p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform EGF-like ligands UBB(153-228) UBC(609-684) NCOR1 TAB2 RPS27A(1-76) ERBB4s80:TAB2:NCOR1:GFAP geneNCOR1 ERBB4m80ERBB4jmAcyt2s80 ERBB4jmAcyt2s80 ERBB4 JM-B CYT-1 isoform Neuregulins ESR1:ESTGERBB4jmAcyt2s80 ERBB4s80:p-Y694-STAT5AUBC(77-152) PI3K:p-ERBB4cyt1PGR gene RPS27A(1-76) EGF EGF-like ligands PIK3CA:PIK3R1ERBB4s80:YAP1PSENEN ERBB4s80:TAB2:NCOR1:S100B genep-Y349,Y350-SHC1 YAP1 ADPKRAS NCOR1 HRAS Ub-ERBB4jmAcyt1s80:NEDD4NRG2 ERBB4jmAcyt2s80 UBC(457-532) NCOR1 ATPNCSTN gamma-secretasecomplexEGF-like ligands GRB2-1 p-Y349,Y350-SHC1 PSEN2(1-297) ERBB4jmAcyt2s80 PIK3R1 Neuregulins UBC(381-456) EGF-like ligands p-ERBB4cyt1 homodimers RAF/MAP kinasecascadeUBC(305-380) PSEN1(1-298) p-Y694-STAT5AhomodimerERBB4 homodimersCSN2 geneNeuregulins ERBB4jmAcyt1s80 S100B geneERBB4jmAcyt2m80 ESTG GDPERBB4ERBB4s80Neuregulins CXCL12(22-93)ITCH p21 RAS:GDPp-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ERBB4s80Prolactin receptorsignalingUBC(229-304) ERBB4jmAcyt2s80 GRB2-1 ERBB4 JM-B CYT-1 isoform EGF-like ligands p-Y694-STAT5A Neuregulins CSN2PGRUBC(229-304) UBC(305-380) Signaling by HippoUBB(153-228) ERBB4 JM-A CYT-1 isoform ERBB4jmAcyt2s80 UbERBB4jmAcyt1s80 APH1B p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform NRAS ERBB4jmAcyt1s80 PIK3CA ERBB4jmAcyt1s80 ESTG UBC(1-76) WWP1/ITCHWWOX NRG1 ADPERBB4m80 EGFR TAB2 ERBB4jmAcyt1s80 EGF NEDD4ERBB4jmAcyt1s80 UBB(77-152) Neuregulins p-ERBB4cyt1 homodimers UBB(1-76) ERBB4jmAcyt1s80dimerERBB4:EGFRheterodimerNRAS Neuregulins ITCH p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform UBC(609-684) p-ERBB4cyt1 homodimers p-Y349,350-SHC1:p-ERBB4APH1A RPS27A(1-76) ERBB4s80:p-Y694-STAT5A:CSN2 gene2044, 726535, 9, 16, 22, 29...13, 356, 19, 36, 45, 47...1, 33, 63432, 18, 243


Description

ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR i.e. HER1), ERBB2 (HER2 i.e. NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).

ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation, but their downstream signaling and physiological significance have not been studied.


All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).

The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).

Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. ERBB4 plays and important role in the development of the nervous system. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells, of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).
In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).
ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Activation of ERBB4 in breast cancer cell lines leads to JNK-dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka-Cook et al. 2006).

WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009). View original pathway at:Reactome.

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Pathway is converted from Reactome ID: 1236394
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Reactome version: 66
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Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  57. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC
  58. Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA, McCall W, Sgagias MK, Cowan KH, Earp HS.; ''Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.''; PubMed Europe PMC
  59. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL, Attisano L.; ''The Hippo pathway regulates Wnt/beta-catenin signaling.''; PubMed Europe PMC
  60. 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.''; PubMed Europe PMC
  61. Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS.; ''The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation.''; PubMed Europe PMC
  62. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE.; ''The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone.''; PubMed Europe PMC
  63. Paoletti P, Bellone C, Zhou Q.; ''NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.''; PubMed Europe PMC
  64. Mitchell RM, Janssen MJ, Karavanova I, Vullhorst D, Furth K, Makusky A, Markey SP, Buonanno A.; ''ErbB4 reduces synaptic GABAA currents independent of its receptor tyrosine kinase activity.''; PubMed Europe PMC
  65. Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMed Europe PMC
  66. Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, Lai C, Mei L, Holmes TC, Gandhi SP, Xu X.; ''Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity.''; PubMed Europe PMC
  67. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC
  68. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC
  69. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M.; ''Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level.''; PubMed Europe PMC
  70. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC
  71. Omerovic J, Santangelo L, Puggioni EM, Marrocco J, Dall'Armi C, Palumbo C, Belleudi F, Di Marcotullio L, Frati L, Torrisi MR, Cesareni G, Gulino A, Alimandi M.; ''The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.''; PubMed Europe PMC
  72. Oh H, Irvine KD.; ''Yorkie: the final destination of Hippo signaling.''; PubMed Europe PMC
  73. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC
  74. Cohen BD, Green JM, Foy L, Fell HP.; ''HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers.''; PubMed Europe PMC
  75. Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y.; ''Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.''; PubMed Europe PMC
  76. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J.; ''TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner.''; PubMed Europe PMC
  77. Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE.; ''The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101606view11:47, 1 November 2018ReactomeTeamreactome version 66
101143view21:33, 31 October 2018ReactomeTeamreactome version 65
100671view20:06, 31 October 2018ReactomeTeamreactome version 64
100221view16:51, 31 October 2018ReactomeTeamreactome version 63
99772view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99330view12:47, 31 October 2018ReactomeTeamreactome version 62
94018view13:51, 16 August 2017ReactomeTeamreactome version 61
93637view11:29, 9 August 2017ReactomeTeamreactome version 61
87122view18:39, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86752view09:25, 11 July 2016ReactomeTeamreactome version 56
83405view11:08, 18 November 2015ReactomeTeamVersion54
81605view13:08, 21 August 2015ReactomeTeamVersion53
77063view08:36, 17 July 2014ReactomeTeamFixed remaining interactions
76768view12:13, 16 July 2014ReactomeTeamFixed remaining interactions
76091view10:15, 11 June 2014ReactomeTeamRe-fixing comment source
75802view11:34, 10 June 2014ReactomeTeamReactome 48 Update
75153view14:10, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74800view08:53, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADAM17 ProteinP78536 (Uniprot-TrEMBL)
ADAM17ComplexR-HSA-1251963 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activation of NMDA

receptors and

postsynaptic events
PathwayR-HSA-442755 (Reactome) NMDA receptors are a subtype of ionotropic glutamate receptors that are specifically activated by a glutamate agonist N-methyl-D-aspartate (NMDA). Activation of NMDA receptors involves opening of the ion channel that allows the influx of Ca2+. NMDA receptors are central to activity dependent changes in synaptic strength and are predominantly involved in the synaptic plasticity that pertains to learning and memory. A unique feature of NMDA receptors, unlike other glutamate receptors, is the requirement for dual activation, both voltage-dependent and ligand-dependent activation. The ligand-dependent activation of NMDA receptors requires co-activation by two ligands, glutamate and glycine. However, at resting membrane potential, the pore of ligand-bound NMDA receptors is blocked by Mg2+. The voltage dependent Mg2+ block is relieved upon depolarization of the post-synaptic membrane. NMDA receptors are coincidence detectors, and are activated only if there is a simultaneous activation of both pre- and post-synaptic cell. Upon activation, NMDA receptors allow the influx of Ca2+ that initiates various molecular signaling cascades involved in the processes of learning and memory. For review, please refer to Cohen and Greenberg 2008, Hardingham and Bading 2010, and Paoletti et al. 2013.
CSN2 gene ProteinENSG00000135222 (Ensembl)
CSN2 geneGeneProductENSG00000135222 (Ensembl)
CSN2ProteinP05814 (Uniprot-TrEMBL)
CXCL12 gene ProteinENSG00000107562 (Ensembl)
CXCL12 geneGeneProductENSG00000107562 (Ensembl)
CXCL12(22-93)ProteinP48061 (Uniprot-TrEMBL)
EGF ProteinP01133 (Uniprot-TrEMBL)
EGF-like ligands R-HSA-1233230 (Reactome)
EGF:EGFRComplexR-HSA-179847 (Reactome)
EGFR ProteinP00533 (Uniprot-TrEMBL)
ERBB3-1 ProteinP21860-1 (Uniprot-TrEMBL)
ERBB4 CYT-1 isoforms R-HSA-1233231 (Reactome)
ERBB4 JM-A CYT-1 isoform ProteinQ15303-1 (Uniprot-TrEMBL)
ERBB4 JM-A CYT-2 isoform ProteinQ15303-3 (Uniprot-TrEMBL)
ERBB4 JM-B CYT-1 isoform ProteinQ15303-2 (Uniprot-TrEMBL)
ERBB4 R-HSA-1233235 (Reactome)
ERBB4 homodimersComplexR-HSA-1250221 (Reactome)
ERBB4/ERBB4m80/ERBB4s80ComplexR-HSA-1253281 (Reactome)
ERBB4/m80/s80:WWP1/ITCHComplexR-HSA-1253284 (Reactome)
ERBB4:EGFR heterodimerComplexR-HSA-1977956 (Reactome)
ERBB4:ERBB3 heterodimerComplexR-HSA-1977955 (Reactome)
ERBB4ComplexR-HSA-1233235 (Reactome)
ERBB4_ECDComplexR-HSA-1251970 (Reactome)
ERBB4cyt1 homodimers R-HSA-1250318 (Reactome)
ERBB4jmAcyt1ECD ProteinQ15303-1 (Uniprot-TrEMBL)
ERBB4jmAcyt1m80 ProteinQ15303-1 (Uniprot-TrEMBL)
ERBB4jmAcyt1s80 dimerComplexR-HSA-1252008 (Reactome)
ERBB4jmAcyt1s80 ProteinQ15303-1 (Uniprot-TrEMBL)
ERBB4jmAcyt1s80:NEDD4ComplexR-HSA-1973959 (Reactome)
ERBB4jmAcyt2ECD ProteinQ15303-3 (Uniprot-TrEMBL)
ERBB4jmAcyt2m80 ProteinQ15303-3 (Uniprot-TrEMBL)
ERBB4jmAcyt2s80 ProteinQ15303-3 (Uniprot-TrEMBL)
ERBB4m80 R-HSA-1251960 (Reactome)
ERBB4m80ComplexR-HSA-1251960 (Reactome)
ERBB4s80 R-HSA-1251980 (Reactome)
ERBB4s80:ESR1:estrogen:CXCL12 geneComplexR-HSA-8954210 (Reactome)
ERBB4s80:ESR1:estrogen:PGR geneComplexR-HSA-8954204 (Reactome)
ERBB4s80:ESR1:estrogenComplexR-HSA-1254397 (Reactome)
ERBB4s80:MyrG-p-Y419-SRCComplexR-HSA-9612227 (Reactome)
ERBB4s80:TAB2:NCOR1:GFAP geneComplexR-HSA-8954171 (Reactome)
ERBB4s80:TAB2:NCOR1:S100B geneComplexR-HSA-8954176 (Reactome)
ERBB4s80:TAB2:NCOR1ComplexR-HSA-1253326 (Reactome)
ERBB4s80:TAB2:NCOR1ComplexR-HSA-1253328 (Reactome)
ERBB4s80:WWOXComplexR-HSA-1253344 (Reactome)
ERBB4s80:YAP1ComplexR-HSA-1253341 (Reactome)
ERBB4s80:YAP1ComplexR-HSA-1253347 (Reactome)
ERBB4s80:p-Y694-STAT5A:CSN2 geneComplexR-HSA-8954223 (Reactome)
ERBB4s80:p-Y694-STAT5AComplexR-HSA-1254284 (Reactome)
ERBB4s80:p-Y694-STAT5AComplexR-HSA-1254288 (Reactome)
ERBB4s80ComplexR-HSA-1251980 (Reactome)
ERBB4s80ComplexR-HSA-1252016 (Reactome)
ERBB4s80ComplexR-HSA-1254403 (Reactome)
ESR1 ProteinP03372 (Uniprot-TrEMBL)
ESR1:ESTGComplexR-HSA-1254381 (Reactome)
ESTG MetaboliteCHEBI:50114 (ChEBI)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GFAP gene ProteinENSG00000131095 (Ensembl)
GFAP geneGeneProductENSG00000131095 (Ensembl)
GFAPProteinP14136 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2:SOS1:p-Y349,350-SHC1:p-ERBB4ComplexR-HSA-1250382 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
ITCH ProteinQ96J02 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEDD4 ProteinP46934 (Uniprot-TrEMBL)
NEDD4ProteinP46934 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NRG1 R-HSA-1233225 (Reactome)
NRG1/2:ERBB3ComplexR-HSA-1247495 (Reactome)
NRG2 ProteinO14511 (Uniprot-TrEMBL)
NRGs/EGF-like ligands:ERBB4ComplexR-HSA-1236393 (Reactome)
NRGs/EGF-like ligandsComplexR-HSA-1233236 (Reactome)
Neuregulins R-HSA-1227957 (Reactome)
PGR gene ProteinENSG00000082175 (Ensembl)
PGR geneGeneProductENSG00000082175 (Ensembl)
PGRProteinP06401 (Uniprot-TrEMBL)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K:p-ERBB4cyt1ComplexR-HSA-1250373 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CA:PIK3R1ComplexR-HSA-1806218 (Reactome)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PSEN1(1-298) ProteinP49768 (Uniprot-TrEMBL)
PSEN1(299-467) ProteinP49768 (Uniprot-TrEMBL)
PSEN2(1-297) ProteinP49810 (Uniprot-TrEMBL)
PSEN2(298-448) ProteinP49810 (Uniprot-TrEMBL)
PSENEN ProteinQ9NZ42 (Uniprot-TrEMBL)
Prolactin receptor signalingPathwayR-HSA-1170546 (Reactome) Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).

PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010).

PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).

Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001).
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
S100B gene ProteinENSG00000160307 (Ensembl)
S100B geneGeneProductENSG00000160307 (Ensembl)
S100BProteinP04271 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1:p-ERBB4ComplexR-HSA-1250359 (Reactome)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
Signaling by HippoPathwayR-HSA-2028269 (Reactome) Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).

There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).

In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.

Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).

In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.

Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010).

TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB2:NCOR1ComplexR-HSA-1253312 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-ERBB4:WWP1/ITCHComplexR-HSA-1253293 (Reactome)
Ub-ERBB4jmAcyt1s80:NEDD4ComplexR-HSA-1977297 (Reactome)
UbComplexR-HSA-113595 (Reactome)
WWOX ProteinQ9NZC7 (Uniprot-TrEMBL)
WWOXProteinQ9NZC7 (Uniprot-TrEMBL)
WWP1 ProteinQ9H0M0 (Uniprot-TrEMBL)
WWP1/ITCHComplexR-HSA-1253275 (Reactome)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1- and WWTR1

(TAZ)-stimulated

gene expression
PathwayR-HSA-2032785 (Reactome) YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010).
YAP1ProteinP46937 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexR-HSA-157343 (Reactome)
p-ERBB4 JM-A homodimersComplexR-HSA-1843077 (Reactome)
p-ERBB4 homodimersComplexR-HSA-1250341 (Reactome)
p-ERBB4cyt1 homodimersComplexR-HSA-1250351 (Reactome)
p-ERBB4cyt1 homodimers R-HSA-1250351 (Reactome)
p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform ProteinQ15303-2 (Uniprot-TrEMBL)
p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform ProteinQ15303-1 (Uniprot-TrEMBL)
p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform ProteinQ15303-3 (Uniprot-TrEMBL)
p-Y349,350-SHC1:p-ERBB4ComplexR-HSA-1250343 (Reactome)
p-Y349,Y350-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y694-STAT5A homodimerComplexR-HSA-507927 (Reactome)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM17mim-catalysisR-HSA-1251992 (Reactome)
ADPArrowR-HSA-1250315 (Reactome)
ADPArrowR-HSA-1250348 (Reactome)
ADPArrowR-HSA-1250370 (Reactome)
ATPR-HSA-1250315 (Reactome)
ATPR-HSA-1250348 (Reactome)
ATPR-HSA-1250370 (Reactome)
CSN2 geneR-HSA-1254290 (Reactome)
CSN2 geneR-HSA-8954224 (Reactome)
CSN2ArrowR-HSA-1254290 (Reactome)
CXCL12 geneR-HSA-8954199 (Reactome)
CXCL12 geneR-HSA-8954207 (Reactome)
CXCL12(22-93)ArrowR-HSA-8954199 (Reactome)
EGF:EGFRR-HSA-1977959 (Reactome)
ERBB4 homodimersArrowR-HSA-1250220 (Reactome)
ERBB4 homodimersR-HSA-1250315 (Reactome)
ERBB4 homodimersmim-catalysisR-HSA-1250315 (Reactome)
ERBB4/ERBB4m80/ERBB4s80R-HSA-1253300 (Reactome)
ERBB4/m80/s80:WWP1/ITCHArrowR-HSA-1253300 (Reactome)
ERBB4/m80/s80:WWP1/ITCHR-HSA-1253282 (Reactome)
ERBB4/m80/s80:WWP1/ITCHmim-catalysisR-HSA-1253282 (Reactome)
ERBB4:EGFR heterodimerArrowR-HSA-1977959 (Reactome)
ERBB4:ERBB3 heterodimerArrowR-HSA-1977958 (Reactome)
ERBB4R-HSA-1236398 (Reactome)
ERBB4_ECDArrowR-HSA-1251992 (Reactome)
ERBB4jmAcyt1s80 dimerR-HSA-1973956 (Reactome)
ERBB4jmAcyt1s80:NEDD4ArrowR-HSA-1973956 (Reactome)
ERBB4jmAcyt1s80:NEDD4R-HSA-1977296 (Reactome)
ERBB4jmAcyt1s80:NEDD4mim-catalysisR-HSA-1977296 (Reactome)
ERBB4m80ArrowR-HSA-1251992 (Reactome)
ERBB4m80R-HSA-1251997 (Reactome)
ERBB4s80:ESR1:estrogen:CXCL12 geneArrowR-HSA-8954199 (Reactome)
ERBB4s80:ESR1:estrogen:CXCL12 geneArrowR-HSA-8954207 (Reactome)
ERBB4s80:ESR1:estrogen:PGR geneArrowR-HSA-1254392 (Reactome)
ERBB4s80:ESR1:estrogen:PGR geneArrowR-HSA-8954208 (Reactome)
ERBB4s80:ESR1:estrogenArrowR-HSA-1254386 (Reactome)
ERBB4s80:ESR1:estrogenR-HSA-8954207 (Reactome)
ERBB4s80:ESR1:estrogenR-HSA-8954208 (Reactome)
ERBB4s80:MyrG-p-Y419-SRCTBarR-HSA-1252013 (Reactome)
ERBB4s80:TAB2:NCOR1:GFAP geneArrowR-HSA-8954185 (Reactome)
ERBB4s80:TAB2:NCOR1:GFAP geneTBarR-HSA-1253321 (Reactome)
ERBB4s80:TAB2:NCOR1:S100B geneArrowR-HSA-8954182 (Reactome)
ERBB4s80:TAB2:NCOR1:S100B geneTBarR-HSA-8954179 (Reactome)
ERBB4s80:TAB2:NCOR1ArrowR-HSA-1253319 (Reactome)
ERBB4s80:TAB2:NCOR1ArrowR-HSA-1253325 (Reactome)
ERBB4s80:TAB2:NCOR1R-HSA-1253319 (Reactome)
ERBB4s80:TAB2:NCOR1R-HSA-8954182 (Reactome)
ERBB4s80:TAB2:NCOR1R-HSA-8954185 (Reactome)
ERBB4s80:WWOXArrowR-HSA-1253343 (Reactome)
ERBB4s80:YAP1ArrowR-HSA-1254248 (Reactome)
ERBB4s80:YAP1ArrowR-HSA-1254251 (Reactome)
ERBB4s80:YAP1R-HSA-1254248 (Reactome)
ERBB4s80:p-Y694-STAT5A:CSN2 geneArrowR-HSA-1254290 (Reactome)
ERBB4s80:p-Y694-STAT5A:CSN2 geneArrowR-HSA-8954224 (Reactome)
ERBB4s80:p-Y694-STAT5AArrowR-HSA-1254285 (Reactome)
ERBB4s80:p-Y694-STAT5AArrowR-HSA-1254291 (Reactome)
ERBB4s80:p-Y694-STAT5AR-HSA-1254285 (Reactome)
ERBB4s80:p-Y694-STAT5AR-HSA-8954224 (Reactome)
ERBB4s80ArrowR-HSA-1251997 (Reactome)
ERBB4s80ArrowR-HSA-1252013 (Reactome)
ERBB4s80ArrowR-HSA-1254376 (Reactome)
ERBB4s80R-HSA-1252013 (Reactome)
ERBB4s80R-HSA-1253325 (Reactome)
ERBB4s80R-HSA-1253343 (Reactome)
ERBB4s80R-HSA-1254251 (Reactome)
ERBB4s80R-HSA-1254291 (Reactome)
ERBB4s80R-HSA-1254376 (Reactome)
ERBB4s80R-HSA-1254386 (Reactome)
ESR1:ESTGR-HSA-1254386 (Reactome)
GDPArrowR-HSA-1250383 (Reactome)
GFAP geneR-HSA-1253321 (Reactome)
GFAP geneR-HSA-8954185 (Reactome)
GFAPArrowR-HSA-1253321 (Reactome)
GRB2-1:SOS1R-HSA-1250380 (Reactome)
GRB2:SOS1:p-Y349,350-SHC1:p-ERBB4ArrowR-HSA-1250380 (Reactome)
GRB2:SOS1:p-Y349,350-SHC1:p-ERBB4mim-catalysisR-HSA-1250383 (Reactome)
GTPR-HSA-1250383 (Reactome)
NEDD4R-HSA-1973956 (Reactome)
NRG1/2:ERBB3R-HSA-1977958 (Reactome)
NRGs/EGF-like ligands:ERBB4ArrowR-HSA-1236398 (Reactome)
NRGs/EGF-like ligands:ERBB4R-HSA-1250220 (Reactome)
NRGs/EGF-like ligands:ERBB4R-HSA-1977958 (Reactome)
NRGs/EGF-like ligands:ERBB4R-HSA-1977959 (Reactome)
NRGs/EGF-like ligandsR-HSA-1236398 (Reactome)
PGR geneR-HSA-1254392 (Reactome)
PGR geneR-HSA-8954208 (Reactome)
PGRArrowR-HSA-1254392 (Reactome)
PI(3,4,5)P3ArrowR-HSA-1250370 (Reactome)
PI(4,5)P2R-HSA-1250370 (Reactome)
PI3K:p-ERBB4cyt1ArrowR-HSA-1250353 (Reactome)
PI3K:p-ERBB4cyt1mim-catalysisR-HSA-1250370 (Reactome)
PIK3CA:PIK3R1R-HSA-1250353 (Reactome)
R-HSA-1236398 (Reactome) All three ERBB4 isoforms are activated by binding of neuregulins (NRG1, NRG2, NRG3 and NRG4) or EGF like growth factors (betacellulin, epiregulin, HB EGF) to their extracellular domain (Tzahar et al. 1994, Carraway et al. 1997, Elenius et al. 1997, Zhang et al. 1997, Riese et al. 1998, Hayes et al. 2007).
R-HSA-1250220 (Reactome) Ligand stimulated ERBB4 forms homodimers (Sweeney et al. 2000).
R-HSA-1250315 (Reactome) Homodimers of ERBB4 CYT 1 isoforms trans autophosphorylate on six tyrosine residues (three on each monomer) that serve as docking sites for SHC1 (tyrosines Y1188 and 1242 in the isoform ERBB4 JM-A CYT1; tyrosines Y1178 and Y1232 in the isoform ERBB4 JM-B CYT1) and the p85 subunit of PI3K (tyrosine Y1056 in the isoform ERBB4 JM-A CYT1; tyrosine Y1046 in the isoform ERBB4 JM-B CYT1), while ERBB4 CYT2 isoform homodimer trans-autophosphorylates on four SHC1 binding tyrosines (two on each monomer - tyrosines Y1172 and Y1226) (Cohen et al. 1996, Kaushansky et al. 2008).
NRG1-mediated activation of ERBB4 signaling negatively regulates, via an unknown mechanism, phosphorylation of NMDA receptors by SRC. ERBB4 signaling is hyperactivated in schizophrenia, while SRC-mediated phosphorylation of NMDA receptors (NMDARs) is reduced in schizophrenia. (Pitcher et al. 2011, Banerjee et al. 2015).
R-HSA-1250348 (Reactome) After binding ERBB4 homodimers, SHC1 gets phosphorylated on tyrosine residues Y349 and Y350 (Kainulainen et al. 2000).
R-HSA-1250353 (Reactome) p85 subunit of PI3K (PIK3R1) directly binds to phosphorylated ERBB4 CYT1 homodimers through docking tyrosine residues on either ERBB4 JM A CYT1 (tyrosine Y1056) or ERBB4 JM B CYT1 (tyrosine Y1046) isoform (Cohen et al. 1996, Kainulainen et al. 2000, Kaushansky et al. 2008).
R-HSA-1250357 (Reactome) Phosphorylated tyrosine residues in the C-tail of phosphorylated ERBB4 isoform dimers P-ERBB4jmAcyt1, P-ERBB4jmAcyt2 and P-ERBB4jmBcyt1 recruit SHC1 (Cohen et al. 1996, Pinkas-Kramarski et al. 1996, Kaushansky et al. 2008).
R-HSA-1250370 (Reactome) Activated PI3K bound to phosphorylated ERBB4 CYT-1 homodimers converts PIP2 into PIP3, which leads to activation of AKT signaling (Kainulainen et al. 2000).
R-HSA-1250380 (Reactome) Phosphorylated SHC1 bound to phosphorylated ERBB4 homodimers recruits GRB2:SOS1 complex (Kainulainen et al. 2000).
R-HSA-1250383 (Reactome) SOS1 in complex with GRB2 and p-Y349,350-SHC1:p-ERBB4 activates RAS by mediating guanyl nucleotide exchange, which results in the activation of RAF/MAP kinase cascade (Kainulainen et al. 2000).
R-HSA-1251992 (Reactome) Phosphorylated ligand-bound homodimers of ERBB4 JM-A isoforms are cleaved by ADAM17 metalloproteinase to yield ligand-bound ERBB4 extracellular domain and membrane bound ERBB4 fragment of 80 kDa (ERBB4m80) (Rio et al. 2000, Cheng et al. 2003).
R-HSA-1251997 (Reactome) After ERBB4 is cleaved by ADAM17, gamma-secretase complex performs additional cleavage in the transmembrane region of the m80 ERBB4 fragment, releasing the soluble ERBB4 intracellular domain of 80 kDa, known as s80 or E4ICD (Ni et al. 2001).
R-HSA-1252013 (Reactome) The soluble intracellular domain of ERBB4 s80 (E4ICD) is able to translocate from the cytosol to the nucleus (Ni et al. 2001). Translocation of ERBB4s80 to the nucleus is negatively regulated by binding of ERBB4s80 to activated SRC kinase (Ishibashi et al. 2012).
R-HSA-1253282 (Reactome) Upon binding to ERBB4 or its cleavage products m80 and s80, NEDD4 family ligases WWP1 and ITCH ubiquitinate intact and cleaved ERBB4 and target it for degradation (Omerovic et al. 2007, Feng et al. 2009).
R-HSA-1253300 (Reactome) Intact ERBB4 isoforms and their membrane bound and cytosolic cleavage products, m80 and s80, bind NEDD4 family E3 ubiquitin ligases WWP1 and ITCH through WW-binding motifs in the C-tail. This interaction is independent of ligand binding and ERBB4 phosphorylation. CYT1 isoforms of ERBB4 have three WW-binding motifs: PY1, PY2 and PY3. PY2 motif is unique to CYT1 isoforms and overlaps with the PIK3R1 binding site. CYT2 isoform of ERBB4 has two WW-binding motifs: PY1 and PY3. While both CYT1 and CYT2 isoforms of ERBB4 all bind WWP1, CYT1 intracellular domain exhibits higher affinity for WWP1. Based on co-immunoprecipitation experiments in which individual WW-binding motifs of ERBB4 were mutated, Feng et al. established that PY2 had the highest affinity for WWP1, followed by PY3, while PY1 showed the lowest affinity (Omerovic et al. 2007, Feng et al. 2009).
R-HSA-1253319 (Reactome) ERBB4s80 (E4ICD) bound to cytosolic TAB2:NCOR1 complex mediates the translocation of this complex to the nucleus (Sardi et al. 2006).
R-HSA-1253321 (Reactome) Transcription of the GFAP gene, involved in astrocyte differentiation, is inhibited by binding of the ERBB4s80:TAB2:NCOR1 complex to the GFAP promoter (Sardi et al. 2006).
R-HSA-1253325 (Reactome) ERBB4s80 (E4ICD) binds cytosolic TAB2:NCOR1 complex through direct interaction with TAB2 (Sardi et al. 2006).
R-HSA-1253343 (Reactome) WWOX binds to ERBB4s80 through WW-domain binding motifs in the C-tail of ERBB4. Formation of ERBB4s80:WWOX complex competes with the formation of ERBB4:YAP1 complex and prevents translocation of ERBB4s80 to the nucleus. Feng et al. established that WWOX binds with the same affinity to s80CYT1 and s80CYT2, and identified PY3 as the most important WW-domain binding motif for WWOX binding (Aqeilan et al. 2005, Feng et al. 2009, Schuchardt et al. 2013).
R-HSA-1254248 (Reactome) Upon formation of ERBB4s80:YAP1 complex in the cytosol, the complex translocates to the nucleus, where it may act as a regulator of transcription (Komuro et al. 2003, Omerovic et al. 2004, Aqeilan et al. 2005).
R-HSA-1254251 (Reactome) ERBB4s80 interacts with a co-transcriptional activator YAP1 through its WW-domain binding motifs in the C-tail. Feng et al. established that the PY2 motif, present in CYT1 isoforms of ERBB4 only, has the highest affinity for YAP1 binding. PY1 and PY3 motifs, shared between CYT1 and CYT2 isoforms, have lower binding affinity for YAP1, with PY1 motif being the least important for YAP1 interaction (Komuro et al. 2003, Omerovic et al. 2004, Feng et al. 2009).
R-HSA-1254285 (Reactome) Formation of cytosolic complex of ERBB4s80 and STAT5A promotes translocation of STAT5A to the nucleus, with ERBB4s80 acting as a nuclear chaperone of STAT5A.
R-HSA-1254290 (Reactome) ERBB4s80:STAT5A complex binds to and stimulates transcription from the beta-casein (CSN2) promoter, and it probably regulates transcription of other lactation-related genes in mammary cells. By over-expressing either human ERBB4cyt1s80 or ERBB4cyt2s80 in mouse mammary cell line HC11 or transgenic mice, Muraoka-Cook et al. showed differential effects of CYT1 and CYT2 isoforms on mammary epithelium. CYT1s80 over-expression decreases cell proliferation, promotes STAT5A-mediated transcription of beta-casein (CSN2) and lactogenic differentiation. In contrast, CYT2s80 over-expression causes epithelial hyperplasia, increased levels of Wnt and beta-catenin, as well as elevated expression of c-myc and cyclin D1 (Muraoka-Cook et al. 2009).
R-HSA-1254291 (Reactome) ERBB4s80 binds STAT5A through STAT5A SH2 domain. This interaction likely depends on STAT5A activation induced by prolactin and mediated by JAK2. Heterodimers of prolactin receptor (PRLR) and JAK2 are activated by prolactin binding, resulting in STAT5 recruitment and phosphorylation, and subsequent formation of phosphorylated STAT5 homodimers. There is evidence that ERBB4 may be part of the PRLR:JAK2 complex and that it may be activated by JAK2-mediated phosphorylation, in the absence of ERBB4 growth factors (Muraoka-Cook et al. 2008).
R-HSA-1254376 (Reactome) Cytosolic ERBB4s80 is able to translocate to mitochondria where its BH3 domain, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006).
R-HSA-1254386 (Reactome) ERBB4s80 forms a complex with activated estrogen receptor ESR1 in the nucleus and acts as a transcriptional co-factor for ESR1 (Zhu et al. 2006).
R-HSA-1254392 (Reactome) The complex of ERBB4s80 and activated estrogen receptor ESR1 promotes transcription of the PGR gene, encoding progesterone receptor (Zhu et al. 2006).
R-HSA-1973956 (Reactome) E3 ubiquitin ligase NEDD4 binds intracellular domain of ERBB4 isoform JM-A CYT1 (ERBB4jmAcyt1s80) produced by ERBB4 cleavage (Zeng et al. 2009).
R-HSA-1977296 (Reactome)