ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).
ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.
In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.
In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.
In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1227986
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Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMedEurope PMCScholia
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Gensler M, Buschbeck M, Ullrich A.; ''Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1.''; PubMedEurope PMCScholia
Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H, Mao Y.; ''Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment.''; PubMedEurope PMCScholia
Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX.; ''Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.''; PubMedEurope PMCScholia
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Batzer AG, Blaikie P, Nelson K, Schlessinger J, Margolis B.; ''The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor.''; PubMedEurope PMCScholia
Qiu C, Lienhard S, Hynes NE, Badache A, Leahy DJ.; ''Memo is homologous to nonheme iron dioxygenases and binds an ErbB2-derived phosphopeptide in its vestigial active site.''; PubMedEurope PMCScholia
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Castro NE, Lange CA.; ''Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.''; PubMedEurope PMCScholia
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Kamalati T, Jolin HE, Fry MJ, Crompton MR.; ''Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation.''; PubMedEurope PMCScholia
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.
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.
E3 ubiquitin ligase Cullin-5 (CUL5) is recruited to the ERBB2 site at the plasma membrane and ubiquitinates ERBB2 in an HSP90-dependent way, targeting it for degradation. Ubiquitination of ERBB2 by CUL5 appears to be independent of CUL5 adaptor proteins ElonginB and ElonginC.
RNF41 ubiquitinates activated ERBB3, thereby downregulating ERBB3-mediated signaling. This reaction is part of a negative feedback loop in ERBB2:ERBB3 signaling.
MATK (also known as CHK or CSK homologous kinase) binds to ERBB2 through phosphorylated tyrosine residue Y1253 in the C-tail of ERBB2 and, through an unknown mechanism, inhibits ERBB2 downstream signaling.
Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) directly bound to phosphorylated ERBB2:ERBB4cyt1 heterodimer, resulting in the assembly of an active PI3K complex.
Phosphorylation of ERBB2 on tyrosine residue Y877 by SRC family kinases significantly increases trans-autophosphorylation rate of ERBB2 heterodimers, presumably by enabling the kinase domain of ERBB2 to achieve a conformation that positively affects ERBB2 kinase activity. The downstream signaling of phosphorylated ERBB2 heterodimers that are phosphorylated on Y877 of ERBB2, in addition to the known trans-autophosphorylation sites, has not been studied extensively; it is assumed that the behavior of Y877-phosphorylated ERBB2 heterodimers is qualitatively similar to the behavior of trans-autophosphorylated ERBB2 heterodimers which do not harbor this modification.
SOS1 bound to GRB2 in complex with any of the phosphorylated ERBB2:ERBB4 heterodimers catalyzes guanyl-nucleotide exchange on RAS, leading to the activation of the MAP kinase cascade.
Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR.
ERBB2, which does not bind any known ligand, is activated through formation of a heterodimer with another ligand-activated ERBB family member. ERBB2 heterodimerization partners are EGF-stimulated EGFR (Wada et al. 1990, Karunagaran et al. 1996), ERBB3 stimulated by neuregulins NRG1 or NRG2 (Pinkas-Kramarski et al. 1996), and ERBB4 stimulated by neuregulins or EGF-like ligands (Li et al. 2007). In the process of dimerization, ERBB2 dissociates from chaperone proteins HSP90 and CDC37 (Xu et al 2001, Citri et al. 2004). Activated ERBB2 also dissociates from ERBB2IP, the protein reponsible for proper localization of ERBB2 to basolateral membranes of epithelial cells (Borg et al. 2000).
SOS1 bound to GRB2 in complex with phosphorylated ERBB2:EGFR heterodimer catalyzes guanyl-nucleotide exchange on RAS, leading to activation of the MAP kinase cascade.
Dissociation of HSP90 from ERBB2 upon formation of ERBB2 heterodimers (with either EGFR, ERBB3 or ERBB4) enables phosphorylation of ERBB2 on the tyrosine residue Y877, mediated by one of SRC family kinases - SRC, FYN or YES1. Although not a mandatory prerequisite of ERBB2 catalytic activity, the phosphorylation at Y877 significantly increases the kinase activity of ERBB2.
Once bound to ERBB2 heterodimers, SHC1 is phosphorylated on tyrosine residues by the tyrosine kinase activity of either ERBB2 or its heterodimerization partners EGFR and ERBB4.
Membrane associated p85 subunit of PI3K (PIK3R1) binds to phosphorylated tyrosine residues of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) in complex with ERBB2.
p85 subunit of PI3K (PIK3R1) directly binds to any of the two phosphorylated ERBB4 CYT1 isoforms in complex with ERBB2 through interaction with a phosphorylated tyrosine residue in the C-tail of ERBB4 CYT1 (Y1056 in ERBB4 JM-A CYT1; Y1046 in ERBB4 JM-B CYT1).
E3 ubiquitin ligase CHIP (STUB1) mediates ERBB2 ubiquitination by associating with the ERBB2 indirectly, through the chaperone protein HSP90. CHIP (STUB1) ubiquitinates both ERBB2 and HSP90, leading to their proteasome-dependent degradation. Ubiquitination of ERBB2 by CHIP (STUB1) is independent of ERBB2 activation.
SHC1 binds phosphorylated ERBB2:EGFR heterodimers through phosphorylated tyrosine residues on either ERBB2 (Y1196, Y1221, Y1222 and Y1248) or EGFR (Y1148 and Y1173). Heterodimers of ERBB2 and ERBB3 recruit SHC1 through a phosphorylated tyrosine residue Y1328 in the C-tail of ERBB3. Heterodimers of ERBB2 and ERBB4 isoforms recruit SHC1 through phosphorylated tyrosines in the C-tail of etiher ERBB2 (Y1196, Y1221, Y1222 and Y1248) or ERBB4 (Y1188 and Y1242 in ERBB4 JM-A CYT1 isoform; Y1178 and Y1232 in ERBB4 JM-B CYT1 isoform; Y1172 and Y1226 in ERBB4 JM-A CYT2 isoform). Association of SHC1 with ERBB2:EGFR and ERBB2:ERBB3 heterodimers was demonstrated in engineered mouse 32D cells in which human ERBB2, EGFR and ERBB3 were expressed. Therefore, these experiments showed association of human ERBB receptor dimers and mouse Shc1. In the case of ERBB2:ERBB4 heterodimers, direct evidence, involving human proteins only, is available.
Dimers of ERBB2 and EGF-bound EGFR trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 tyrosine residues to form phosphorylated heterodimers that activate downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990, Helin et al. 1991).
In heterodimers of ERBB2 and neuregulin-stimulated ERBB3, ERBB2 phosphorylates ERBB3 on tyrosine residues that serve as docking sites for p85 subunit of PI3K (Y1054, Y1197, Y1222, Y1224, Y1260, Y1276 and Y1289), as well as SHC1 (Y1328) and GRB7 (Y1199 and Y1262). Since ERBB3 lacks catalytic activity, it cannot phosphorylate ERBB2. Hovewer, since ERBB2:ERBB3 heterodimers usually oligomerize on the cell surface, ERBB2 can become trans-autophosphorylated by and adjacent ERBB2 protein. It is not known if ERBB2 in the ERBB2:ERBB3 hetero-oligomer is phosphorylated on all conserved tyrosine residues and if the phosphorylation status of ERBB2 in the ERBB2:ERBB3 hetero-oligoimer significantly affects signaling (Li et al. 2007, Pinkas-Kramarski et al. 1996, Prigent et al. 1994, Vijapurkar et al. 2003, Wallasch et al. 1995).
Heterodimers of ERBB2 and ERBB4 trans-autophosphorylate on tyrosine residues that serve as docking sites for PLC-gamma, GRB2 and SHC1, as well as p85 subunit of PI3K (PIK3R1) in the case of ERBB2 heterodimers with ERBB4 CYT1 isoforms (ERBB4cyt1) - ERBB4 JM-A CYT1 and ERBB4 JM-B-CYT1 (Li et al. 2007, Kaushansky et al. 2008, Hazan et al. 1990, Cohen et al. 1996).
Activated AKT phosphorylates USP8, thereby stabilizing it and allowing it to deubiquitinate NRDP1, which results in increased NRDP1 level and downregulation of ERBB3. This represents a negative feedback loop in ERBB3-mediated signaling.
GAB1 in complex with GRB2 is recruited to activated ERBB2:EGFR heterodimer through phosphorylated tyrosine residues that serve as docking sites for GRB2.
Phosphorylated ERBB2:EGFR heterodimer recruits GRB2:SOS1 complex through phosphorylated tyrosine residues on either ERBB2 or EGFR that serve as direct docking sites for GRB2.
Activated PI3K complex directly bound to phosphorylated heterodimer of ERBB2 and ERBB3 phosphorylates PIP2 and converts it into PIP3, leading to activation of AKT signaling.
ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example.
In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.
In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1.
In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1227986
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DataNodes
p-EGFR p-ERBB2 GRB2 GAB1
PI3Kp-EGFR p-ERBB2 GRB2 GAB1
PIK3R1p-EGFR p-ERBB2 GRB2
GAB1p-EGFR p-ERBB2 GRB2
SOS1p-EGFR p-ERBB2
PLCG1ERBB2IP HSP90
CDC37SOS1 p-Y349,350-SHC1
Phosphorylated ERBB2 heterodimersUb-p-10Y-ERBB3
p-ERBB2p-10Y-ERBB3 p-ERBB2
GRB7p-10Y-ERBB3 p-ERBB2
RNF41p-ERBB3 p-ERBB2
PI3Kp-ERBB3 p-ERBB2
PIK3R1p-ERBB4 p-ERBB2 GRB2
SOS1p-ERBB4cyt1 p-ERBB2
PI3Kp-ERBB4cyt1 p-ERBB2
PIK3R1ERBB2IP HSP90
CDC37ERBB2IP Ub-HSP90
CDC37Annotated Interactions
p-EGFR p-ERBB2 GRB2 GAB1
PI3Kp-EGFR p-ERBB2 GRB2 GAB1
PIK3R1p-EGFR p-ERBB2 GRB2
GAB1p-EGFR p-ERBB2 GRB2
SOS1p-EGFR p-ERBB2
PLCG1p-EGFR p-ERBB2
PLCG1ERBB2IP HSP90
CDC37ERBB2IP HSP90
CDC37ERBB2IP HSP90
CDC37SOS1 p-Y349,350-SHC1
Phosphorylated ERBB2 heterodimersUb-p-10Y-ERBB3
p-ERBB2p-10Y-ERBB3 p-ERBB2
RNF41p-10Y-ERBB3 p-ERBB2
RNF41p-ERBB3 p-ERBB2
PI3Kp-ERBB3 p-ERBB2
PIK3R1p-ERBB4 p-ERBB2 GRB2
SOS1p-ERBB4cyt1 p-ERBB2
PI3Kp-ERBB4cyt1 p-ERBB2
PIK3R1In heterodimers of ERBB2 and neuregulin-stimulated ERBB3, ERBB2 phosphorylates ERBB3 on tyrosine residues that serve as docking sites for p85 subunit of PI3K (Y1054, Y1197, Y1222, Y1224, Y1260, Y1276 and Y1289), as well as SHC1 (Y1328) and GRB7 (Y1199 and Y1262). Since ERBB3 lacks catalytic activity, it cannot phosphorylate ERBB2. Hovewer, since ERBB2:ERBB3 heterodimers usually oligomerize on the cell surface, ERBB2 can become trans-autophosphorylated by and adjacent ERBB2 protein. It is not known if ERBB2 in the ERBB2:ERBB3 hetero-oligomer is phosphorylated on all conserved tyrosine residues and if the phosphorylation status of ERBB2 in the ERBB2:ERBB3 hetero-oligoimer significantly affects signaling (Li et al. 2007, Pinkas-Kramarski et al. 1996, Prigent et al. 1994, Vijapurkar et al. 2003, Wallasch et al. 1995).
Heterodimers of ERBB2 and ERBB4 trans-autophosphorylate on tyrosine residues that serve as docking sites for PLC-gamma, GRB2 and SHC1, as well as p85 subunit of PI3K (PIK3R1) in the case of ERBB2 heterodimers with ERBB4 CYT1 isoforms (ERBB4cyt1) - ERBB4 JM-A CYT1 and ERBB4 JM-B-CYT1 (Li et al. 2007, Kaushansky et al. 2008, Hazan et al. 1990, Cohen et al. 1996).