Signaling by ERBB4 (Homo sapiens)
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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. 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). 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).
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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1236394
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. 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). 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).
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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1236394
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- Ahrens S, Jaramillo S, Yu K, Ghosh S, Hwang GR, Paik R, Lai C, He M, Huang ZJ, Li B.; ''ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection.''; PubMed Europe PMC Scholia
- 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 Scholia
- Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J.; ''Identification of autophosphorylation sites of HER2/neu.''; PubMed Europe PMC Scholia
- Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS.; ''Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.''; PubMed Europe PMC Scholia
History
View all... |
External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| ADAM17 | Protein | P78536 (Uniprot-TrEMBL)  | |
| ADAM17 | Complex | REACT_116419 (Reactome) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| APH1A | Protein | Q96BI3 (Uniprot-TrEMBL) | |
| APH1B | Protein | Q8WW43 (Uniprot-TrEMBL) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Betacellulin | Protein | P35070 (Uniprot-TrEMBL) | |
| CSN2 | Protein | P05814 (Uniprot-TrEMBL) | |
| CXCL12 | Protein | P48061 (Uniprot-TrEMBL) | |
| EGF EGFR | Complex | REACT_9893 (Reactome) | |
| EGF | Protein | P01133 (Uniprot-TrEMBL) | |
| EGFR | Protein | P00533 (Uniprot-TrEMBL) | |
| ERBB3-1 | Protein | P21860-1 (Uniprot-TrEMBL) | |
| ERBB4 EGFR heterodimer | Complex | REACT_116654 (Reactome) | |
| ERBB4 ERBB3 heterodimer | Complex | REACT_117805 (Reactome) | |
| ERBB4 JM-A CYT-1 isoform | Protein | Q15303-1 (Uniprot-TrEMBL) | |
| ERBB4 JM-A CYT-2 isoform | Protein | Q15303-3 (Uniprot-TrEMBL) | |
| ERBB4 JM-B CYT-1 isoform | Protein | Q15303-2 (Uniprot-TrEMBL) | |
| ERBB4 homodimers | REACT_117065 (Reactome) | ||
| ERBB4/ERBB4m80/ERBB4s80 | Complex | REACT_116511 (Reactome) | |
| ERBB4/m80/s80 WWP1/ITCH | Complex | REACT_117195 (Reactome) | |
| ERBB4 | Protein | REACT_116255 (Reactome) | |
| ERBB4_ECD | Complex | REACT_117885 (Reactome) | |
| ERBB4jmAcyt1m80 | Protein | Q15303-1 (Uniprot-TrEMBL) | |
| ERBB4jmAcyt1s80 NEDD4 | Complex | REACT_116714 (Reactome) | |
| ERBB4jmAcyt1s80 | Protein | Q15303-1 (Uniprot-TrEMBL) | |
| ERBB4jmAcyt1s80 dimer | Complex | REACT_116961 (Reactome) | |
| ERBB4jmAcyt2m80 | Protein | Q15303-3 (Uniprot-TrEMBL) | |
| ERBB4jmAcyt2s80 | Protein | Q15303-3 (Uniprot-TrEMBL) | |
| ERBB4m80 | Complex | REACT_116769 (Reactome) | |
| ERBB4s80 ESR1 | Complex | REACT_117209 (Reactome) | |
| ERBB4s80 STAT5A | Complex | REACT_116515 (Reactome) | |
| ERBB4s80 STAT5A | Complex | REACT_117283 (Reactome) | |
| ERBB4s80
TAB2 NCOR1 | Complex | REACT_117194 (Reactome) | |
| ERBB4s80
TAB2 NCOR1 | Complex | REACT_117347 (Reactome) | |
| ERBB4s80 WWOX | Complex | REACT_116574 (Reactome) | |
| ERBB4s80 YAP1 | Complex | REACT_116244 (Reactome) | |
| ERBB4s80 YAP1 | Complex | REACT_117816 (Reactome) | |
| ERBB4s80 | Complex | REACT_116484 (Reactome) | |
| ERBB4s80 | Complex | REACT_116936 (Reactome) | |
| ERBB4s80 | Complex | REACT_117313 (Reactome) | |
| ESR1 estrogen | Complex | REACT_117017 (Reactome) | |
| ESR1 | Protein | P03372 (Uniprot-TrEMBL) | |
| ESTG | Metabolite | CHEBI:50114 (ChEBI) | |
| Epiregulin | Protein | O14944 (Uniprot-TrEMBL) | |
| GDP | Metabolite | CHEBI:17552 (ChEBI) | |
| GDP | Metabolite | CHEBI:17552 (ChEBI) | |
| GFAP | Protein | P14136 (Uniprot-TrEMBL) | |
| GRB2
SOS1 p-Y349,350-SHC1 p-ERBB4 | Complex | REACT_116366 (Reactome) | |
| GRB2 SOS1 | Complex | REACT_4435 (Reactome) | |
| GRB2-1 | Protein | P62993-1 (Uniprot-TrEMBL) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| HBEGF | Protein | Q99075 (Uniprot-TrEMBL) | |
| HRAS | Protein | P01112 (Uniprot-TrEMBL) | |
| ITCH | Protein | Q96J02 (Uniprot-TrEMBL) | |
| KRAS | Protein | P01116 (Uniprot-TrEMBL) | |
| NCOR1 | Protein | O75376 (Uniprot-TrEMBL) | |
| NCSTN | Protein | Q92542 (Uniprot-TrEMBL) | |
| NEDD4 | Protein | P46934 (Uniprot-TrEMBL) | |
| NEDD4 | Protein | P46934 (Uniprot-TrEMBL) | |
| NRAS | Protein | P01111 (Uniprot-TrEMBL) | |
| NRG1 | Protein | Q02297 (Uniprot-TrEMBL) | |
| NRG1-10 | Protein | Q02297-10 (Uniprot-TrEMBL) | |
| NRG1/2 ERBB3 | Complex | REACT_117375 (Reactome) | |
| NRG2 | Protein | O14511 (Uniprot-TrEMBL) | |
| NRGs/EGF-like ligands ERBB4 | REACT_117478 (Reactome) | ||
| NRGs/EGF-like ligands | Protein | REACT_116669 (Reactome) | |
| PGR | Protein | P06401 (Uniprot-TrEMBL) | |
| PI3K p-ERBB4cyt1 | Complex | REACT_117442 (Reactome) | |
| PI | Metabolite | CHEBI:16618 (ChEBI) | |
| PI | Metabolite | CHEBI:18348 (ChEBI) | |
| PIK3CA | Protein | P42336 (Uniprot-TrEMBL) | |
| PIK3CA | Protein | P42336 (Uniprot-TrEMBL) | |
| PIK3R1 p-ERBB4cyt1 | Complex | REACT_117201 (Reactome) | |
| PIK3R1 | Protein | P27986 (Uniprot-TrEMBL) | |
| PIK3R1 | Protein | P27986 (Uniprot-TrEMBL) | |
| PIP3 activates AKT signaling | Pathway | REACT_75829 (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. |
| PSEN2 | Protein | P49810 (Uniprot-TrEMBL) | |
| PSENEN | Protein | Q9NZ42 (Uniprot-TrEMBL) | |
| Prolactin receptor signaling | Pathway | REACT_115697 (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 cascade | Pathway | REACT_634 (Reactome) | The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus. |
| RPS27A | Protein | P62979 (Uniprot-TrEMBL) | |
| S100B | Protein | P04271 (Uniprot-TrEMBL) | |
| SHC1 p-ERBB4 | Complex | REACT_116475 (Reactome) | |
| SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| SOS1 | Protein | Q07889 (Uniprot-TrEMBL) | |
| STAT5A homodimer | Complex | REACT_24376 (Reactome) | |
| TAB2 NCOR1 | Complex | REACT_116523 (Reactome) | |
| TAB2 | Protein | Q9NYJ8 (Uniprot-TrEMBL) | |
| UBA52 | Protein | P62987 (Uniprot-TrEMBL) | |
| UBB | Protein | P0CG47 (Uniprot-TrEMBL) | |
| UBC | Protein | P0CG48 (Uniprot-TrEMBL) | |
| Ub-ERBB4 WWP1/ITCH | Complex | REACT_116798 (Reactome) | |
| Ub-ERBB4jmAcyt1s80 NEDD4 | Complex | REACT_117572 (Reactome) | |
| Ub | Protein | REACT_3316 (Reactome) | |
| WWOX | Protein | Q9NZC7 (Uniprot-TrEMBL) | |
| WWOX | Protein | Q9NZC7 (Uniprot-TrEMBL) | |
| WWP1 | Protein | Q9H0M0 (Uniprot-TrEMBL) | |
| WWP1/ITCH | Protein | REACT_117486 (Reactome) | |
| YAP1 | Protein | P46937 (Uniprot-TrEMBL) | |
| YAP1 | Protein | P46937 (Uniprot-TrEMBL) | |
| Zn2+ | Metabolite | CHEBI:29105 (ChEBI) | |
| gamma-secretase complex | Complex | REACT_5292 (Reactome) | |
| p-ERBB4 JM-A homodimers | Complex | REACT_116984 (Reactome) | |
| p-ERBB4 homodimers | Complex | REACT_117418 (Reactome) | |
| p-ERBB4cyt1 homodimers | Complex | REACT_116404 (Reactome) | |
| p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform | Protein | Q15303-2 (Uniprot-TrEMBL) | |
| p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform | Protein | Q15303-1 (Uniprot-TrEMBL) | |
| p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform | Protein | Q15303-3 (Uniprot-TrEMBL) | |
| p-Y349,350-SHC1 p-ERBB4 | Complex | REACT_117460 (Reactome) | |
| p-Y349,Y350-SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| p-Y694-STAT5A | Protein | P42229 (Uniprot-TrEMBL) | |
| p21 RAS GDP | Complex | REACT_2657 (Reactome) | |
| p21 RAS GTP | Complex | REACT_4782 (Reactome) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADAM17 | mim-catalysis | REACT_115618 (Reactome) | ||
| ADP | Arrow | REACT_115712 (Reactome) | ||
| ADP | Arrow | REACT_115935 (Reactome) | ||
| ADP | Arrow | REACT_115989 (Reactome) | ||
| ATP | REACT_115712 (Reactome) | |||
| ATP | REACT_115935 (Reactome) | |||
| ATP | REACT_115989 (Reactome) | |||
| CXCL12 | Arrow | REACT_115653 (Reactome) | ||
| EGF EGFR | REACT_116135 (Reactome) | |||
| ERBB4 homodimers | REACT_115989 (Reactome) | |||
| ERBB4 homodimers | mim-catalysis | REACT_115989 (Reactome) | ||
| ERBB4/ERBB4m80/ERBB4s80 | REACT_116036 (Reactome) | |||
| ERBB4/m80/s80 WWP1/ITCH | REACT_116054 (Reactome) | |||
| ERBB4/m80/s80 WWP1/ITCH | mim-catalysis | REACT_116054 (Reactome) | ||
| ERBB4 | REACT_115812 (Reactome) | |||
| ERBB4_ECD | Arrow | REACT_115618 (Reactome) | ||
| ERBB4jmAcyt1s80 NEDD4 | REACT_115889 (Reactome) | |||
| ERBB4jmAcyt1s80 NEDD4 | mim-catalysis | REACT_115889 (Reactome) | ||
| ERBB4jmAcyt1s80 dimer | REACT_115758 (Reactome) | |||
| ERBB4m80 | Arrow | REACT_115618 (Reactome) | ||
| ERBB4s80 ESR1 | Arrow | REACT_115653 (Reactome) | ||
| ERBB4s80 STAT5A | Arrow | REACT_116088 (Reactome) | ||
| ERBB4s80
TAB2 NCOR1 | TBar | REACT_115713 (Reactome) | ||
| ERBB4s80 | REACT_115707 (Reactome) | |||
| ERBB4s80 | REACT_115793 (Reactome) | |||
| ERBB4s80 | REACT_115862 (Reactome) | |||
| ERBB4s80 | REACT_116068 (Reactome) | |||
| ERBB4s80 | REACT_116083 (Reactome) | |||
| ESR1 estrogen | REACT_116083 (Reactome) | |||
| GDP | Arrow | REACT_115999 (Reactome) | ||
| GFAP | Arrow | REACT_115713 (Reactome) | ||
| GRB2
SOS1 p-Y349,350-SHC1 p-ERBB4 | mim-catalysis | REACT_115999 (Reactome) | ||
| GRB2 SOS1 | REACT_116037 (Reactome) | |||
| GTP | REACT_115999 (Reactome) | |||
| NEDD4 | REACT_115758 (Reactome) | |||
| NRG1/2 ERBB3 | REACT_115947 (Reactome) | |||
| NRGs/EGF-like ligands ERBB4 | REACT_115947 (Reactome) | |||
| NRGs/EGF-like ligands ERBB4 | REACT_116135 (Reactome) | |||
| NRGs/EGF-like ligands | REACT_115812 (Reactome) | |||
| PGR | Arrow | REACT_115653 (Reactome) | ||
| PI3K p-ERBB4cyt1 | mim-catalysis | REACT_115712 (Reactome) | ||
| PI | Arrow | REACT_115712 (Reactome) | ||
| PIK3CA | REACT_115570 (Reactome) | |||
| PIK3R1 p-ERBB4cyt1 | REACT_115570 (Reactome) | |||
| PIK3R1 | REACT_115722 (Reactome) | |||
| PI | REACT_115712 (Reactome) | |||
| REACT_115552 (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. | |||
| REACT_115558 (Reactome) | The soluble intracellular domain of ERBB4 s80 (E4ICD) is able to translocate from the cytosol to the nucleus. | |||
| REACT_115570 (Reactome) | PI3K subunit p110 (PIK3CA) is recruited by PI3K subunit p85 (PIK3R1) bound to phosphorylated P-ERBB4cyt1 homodimers to form active PI3K. | |||
| REACT_115618 (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). | |||
| REACT_115653 (Reactome) | The complex of ERBB4s80 and activated estrogen receptor ESR1 promotes transcription of estrogen regulated genes NR3C3 (coding for progesterone receptor) and CXCL12 (SDF1). | |||
| REACT_115674 (Reactome) | ERBB4s80 (E4ICD) bound to cytosolic TAB2:NCOR1 complex mediates the translocation of this complex to the nucleus. | |||
| REACT_115707 (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. | |||
| REACT_115712 (Reactome) | Activated PI3K bound to phosphorylated ERBB4 CYT-1 homodimers converts PIP2 into PIP3, which leads to activation of AKT signaling. | |||
| REACT_115713 (Reactome) | Transcription of GFAP and S100B genes, involved in astrocyte differentiation, is inhibited by ERBB4s80:TAB2:NCOR1 complex which binds promoters of GFAP and S100B. | |||
| REACT_115722 (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. | |||
| REACT_115758 (Reactome) | E3 ubiquitin ligase NEDD4 binds intracellular domain of ERBB4 isoform JM-A CYT1 (ERBB4jmAcyt1s80) produced by ERBB4 cleavage. | |||
| REACT_115793 (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). | |||
| REACT_115812 (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. | |||
| REACT_115819 (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. | |||
| REACT_115862 (Reactome) | ERBB4s80 (E4ICD) binds cytosolic TAB2:NCOR1 complex through direct interaction with TAB2. | |||
| REACT_115889 (Reactome) | E3 ubiquitin ligase NEDD4 mediates ubiquitination of ERBB4 JM-A CYT-1 intracellular domain s80 (ERBB4jmAcyt1s80) produced by ERBB4 cleavage. This induces degradation of ERBB4jmAcyt1s80, and decreases the amount of ERBB4jmAcyt1s80 that reaches the nucleus. | |||
| REACT_115908 (Reactome) | Phosphorylated tyrosine residues in the C-tail of phosphorylated ERBB4 isoform dimers P-ERBB4jmAcyt1, P-ERBB4jmAcyt2 and P-ERBB4jmBcyt1 recruit SHC1. | |||
| REACT_115913 (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. | |||
| REACT_115935 (Reactome) | After binding ERBB4 homodimers, SHC1 gets phosphorylated on tyrosine residues Y349 and Y350. | |||
| REACT_115942 (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. | |||
| REACT_115947 (Reactome) | Ligand-stimulated ERBB4 was shown to form heterodimers with ligand-stimulated ERBB3 when human ERBB4 and ERBB3 were exogenously expressed in mouse pro-B-lymphocyte cell line. Heterodimers of ERBB4 and ERBB3 undergo trans-autophosphorylation, but the exact phosphorylation pattern, downstream signaling and physiological significance of these heterodimers have not been studied. | |||
| REACT_115969 (Reactome) | Ligand stimulated ERBB4 forms homodimers. | |||
| REACT_115989 (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). | |||
| REACT_115999 (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. | |||
| REACT_116036 (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. | |||
| REACT_116037 (Reactome) | Phosphorylated SHC1 bound to phosphorylated ERBB4 homodimers recruits GRB2:SOS1 complex. | |||
| REACT_116054 (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. | |||
| REACT_116068 (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. | |||
| REACT_116083 (Reactome) | ERBB4s80 forms a complex with activated estrogen receptor ESR1 in the nucleus and acts as a transcriptional co-factor for ESR1. | |||
| REACT_116088 (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). | |||
| REACT_116135 (Reactome) | Ligand-stimulated ERBB4 was shown to form heterodimers with ligand-stimulated EGFR when human ERBB4 and EGFR were exogenously expressed in mouse fibroblast cell line. Heterodimers of ERBB4 and EGFR undergo trans-autophosphorylation, but the exact phosphorylation pattern, downstream signaling and physiological significance of these heterodimers have not been studied. | |||
| S100B | Arrow | REACT_115713 (Reactome) | ||
| SHC1 p-ERBB4 | REACT_115935 (Reactome) | |||
| SHC1 p-ERBB4 | mim-catalysis | REACT_115935 (Reactome) | ||
| SHC1 | REACT_115908 (Reactome) | |||
| STAT5A homodimer | REACT_115793 (Reactome) | |||
| TAB2 NCOR1 | REACT_115862 (Reactome) | |||
| Ub | REACT_115889 (Reactome) | |||
| Ub | REACT_116054 (Reactome) | |||
| WWOX | REACT_115707 (Reactome) | |||
| WWP1/ITCH | REACT_116036 (Reactome) | |||
| YAP1 | REACT_116068 (Reactome) | |||
| gamma-secretase complex | mim-catalysis | REACT_115913 (Reactome) | ||
| p-ERBB4 homodimers | Arrow | REACT_115989 (Reactome) | ||
| p-ERBB4 homodimers | REACT_115908 (Reactome) | |||
| p-ERBB4cyt1 homodimers | REACT_115722 (Reactome) | |||
| p-Y349,350-SHC1 p-ERBB4 | Arrow | REACT_115935 (Reactome) | ||
| p-Y349,350-SHC1 p-ERBB4 | REACT_116037 (Reactome) | |||
| p21 RAS GDP | REACT_115999 (Reactome) | |||
| p21 RAS GTP | Arrow | REACT_115999 (Reactome) |
