| 1994 |
ErbB3 is a receptor for heregulin (HRG): radiolabeled HRG-beta1 EGF-like domain bound specifically to insect cell-expressed ErbB3 (Kd ~0.85 nM) and to ErbB3-transfected NIH3T3 fibroblasts (Kd ~60 pM). Chemical cross-linking demonstrated direct binding to a 170-180 kDa ErbB3 protein, and HRG stimulated tyrosine phosphorylation of both ErbB3 and co-expressed p185erbB2/neu. |
Radioligand binding assay, chemical cross-linking, immunoprecipitation, tyrosine phosphorylation assay |
The Journal of biological chemistry |
High |
8188716
|
| 1994 |
NDF/heregulin (NDF) stimulates tyrosine phosphorylation of HER3/ErbB3 in breast carcinoma cell lines and HER3-transfected CHO cells, and induces receptor hetero-oligomerization (>400 kDa complex detected by cross-linking and anti-HER3 immunoprecipitation), suggesting NDF is a ligand for HER3. |
Tyrosine phosphorylation assay, 125I-NDF cross-linking, immunoprecipitation |
FEBS letters |
Medium |
8045292
|
| 1995 |
ErbB3 (and ErbB4) are localized at neuromuscular synaptic sites in adult rodent skeletal muscle, remaining concentrated there after denervation, indicating postsynaptic membrane localization independent of innervation. |
Immunohistochemistry with ErbB-specific antibodies in rodent skeletal muscle, denervation experiment |
The EMBO journal |
Medium |
8846777
|
| 1996 |
In cultured rat hepatocytes, heregulin-beta1 (HRGbeta1) binds specifically to ErbB3 (cross-linking confirmed), induces ErbB3 phosphorylation, and decreases ErbB3 protein levels (indicating ligand-induced receptor trafficking/downregulation). Insulin inhibits HRGbeta1 binding and reduces ErbB3 protein levels, revealing insulin-mediated regulation of ErbB3 expression. |
125I-HRGbeta1 binding assay, chemical cross-linking, Western blotting, DNA synthesis assay |
The Journal of biological chemistry |
Medium |
8662847
|
| 1998 |
ErbB3 interacts with the p85 regulatory subunit of PI3K via its YXXM motifs: a single YXXM motif was necessary and sufficient for ErbB3/p85 association, multiple YXXM motifs strengthened the interaction, and the p85 SH3 domain contributed to but was not required for the interaction. The proline-rich region of ErbB3 was not required. |
Yeast two-hybrid with chimeric ErbB3 (EGFR kinase domain fused to ErbB3 C-terminus), ErbB3 deletion and Tyr→Phe site-specific mutants, in vitro binding assay |
The Biochemical journal |
High |
9677338
|
| 2003 |
ErbB3 is constitutively phosphorylated and bound to PI3K in signet-ring cell (dedifferentiated) gastric carcinoma cells. Expression of a constitutively active ErbB2/ErbB3 chimeric receptor in differentiated adenocarcinoma cells induced dedifferentiated phenotypes (loss of cell-cell interaction, high MUC1/DF3 expression), demonstrating that ErbB3 phosphorylation drives dedifferentiated malignant phenotypes. |
Protein purification and identification by mass spectrometry, constitutively active chimeric receptor expression, phenotypic analysis |
Oncogene |
Medium |
12618754
|
| 2005 |
In zebrafish, erbb3 and erbb2 are required for Schwann cell migration and the onset of myelination in vivo. Genetic mutations in erbb3 disrupt Schwann cell proliferation and migration (but not survival), and pharmacological ErbB inhibition at post-migratory stages blocks proliferation and terminal differentiation of myelinating Schwann cells. |
Zebrafish forward genetic screen, BrdU incorporation, time-lapse imaging, pharmacological ErbB inhibition at defined developmental stages |
Current biology : CB |
High |
15797019
|
| 2006 |
ErbB3-dependent signaling through ErbB3/ErbB2 heterodimers enhances tumor cell intravasation and lung metastasis in orthotopic breast cancer models. Increasing ErbB3 expression enhances chemotaxis and invasion responses to heregulin-beta1, while suppression of ErbB3 reduces both intravasation and metastasis with no effect on primary tumor growth or microvessel density. |
Orthotopic injection models, ErbB3 overexpression and siRNA knockdown, chemotaxis/invasion assays, intravasation quantification |
Cancer research |
Medium |
16452197
|
| 2006 |
ErbB3 undergoes nuclear localization in prostate cancer cells; nuclear ErbB3 is significantly more prevalent in hormone-refractory tissues (100%) versus hormone-sensitive tissues (40%), detected by immunohistochemistry of 143 prostate cancer samples and confirmed by subcellular fractionation Western blotting of prostate cancer cell lines. |
Immunohistochemistry on tissue sections and TMA, subcellular fractionation followed by Western blotting |
Clinical cancer research |
Medium |
16675564
|
| 2007 |
MET amplification drives gefitinib resistance by activating ERBB3 (HER3)-dependent PI3K signaling. MET-amplified gefitinib-resistant lung cancer cells show MET-driven HER3 phosphorylation, and combined inhibition of MET restored gefitinib sensitivity. This demonstrated that MET can activate a pathway (ErbB3→PI3K) previously thought specific to EGFR/ErbB family receptors. |
Cell line resistance model, combinatorial kinase inhibition, phosphorylation analysis, MET amplification detected in patient specimens |
Science (New York, N.Y.) |
High |
17463250
|
| 2007 |
Loss-of-function of ERBB3 (aberrant splicing leading to truncated protein) causes lethal congenital contractural syndrome type 2 (LCCS2), an autosomal recessive neurogenic arthrogryposis with anterior horn atrophy, establishing that ERBB3 is essential in vivo for generation of Schwann cell precursors that accompany peripheral motor axons. |
Human genetic mapping, identification of disease-causing ERBB3 splicing mutation in affected families |
American journal of human genetics |
High |
17701904
|
| 2008 |
ErbB3 and ErbB2 are required for amputation-induced proliferation and migration during zebrafish fin regeneration. NRG1 and PI3K functionally interact with ErbB2/ErbB3 in this process; genetic or chemical inhibition of ErbB signaling reduces progenitor proliferation and migration and expression of transcription factors lef1 and msxB. |
Zebrafish genetic and chemical modulation of ErbB2/ErbB3, BrdU labeling, cell migration assays, gene expression analysis |
Developmental biology |
Medium |
19133254
|
| 2009 |
Necl-2 (an immunoglobulin-like cell adhesion molecule) interacts in cis with the extracellular region of ErbB3 (but not ErbB2), reducing ligand-induced ErbB2-catalyzed tyrosine phosphorylation of ErbB3. This inhibitory effect is mediated by the protein-tyrosine phosphatase PTPN13, which interacts with the cytoplasmic tail of Necl-2, resulting in inhibition of ErbB3-mediated Rac and Akt activation and suppression of cancer cell movement and survival. |
Co-immunoprecipitation, domain-specific interaction mapping, siRNA knockdown, Rac/Akt activity assays, cell migration and survival assays |
The Journal of biological chemistry |
Medium |
19561085
|
| 2010 |
Despite lacking several key conserved catalytic residues including the catalytic base aspartate, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region. The ErbB3 kinase domain binds ATP with Kd ~1.1 µM. Crystal structure of ErbB3 kinase bound to an ATP analogue revealed an inactive-like configuration with a shortened αC-helix. QM/MM simulations defined a phosphoryl transfer reaction pathway that does not require the conserved catalytic base. |
In vitro kinase assay, ATP binding assay, X-ray crystallography, quantum mechanics/molecular mechanics (QM/MM) simulation, mutagenesis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
20351256
|
| 2011 |
Nrdp1 (RING finger E3 ubiquitin ligase) preferentially associates with the nascent form of ErbB3 at the endoplasmic reticulum (ER), mediating ligand-independent ubiquitination and degradation of ErbB3 via the ER-associated degradation (ERAD) pathway (VCP/p97-dependent). Blocking ER exit does not affect Nrdp1-mediated ubiquitination, and disruption of VCP/p97 accumulates ubiquitinated ErbB3 without degradation. |
Co-localization at ER, ubiquitination assays, VCP/p97 dominant-negative and siRNA, protein stability assays, fluorescence microscopy |
Molecular and cellular biology |
High |
21576364
|
| 2011 |
Inhibition of PI3K (with XL147) in HER2-overexpressing breast cancer cells causes feedback upregulation of HER3 expression and phosphorylation via FoxO1/FoxO3a transcription factors. Knockdown of FoxO1/FoxO3a suppressed HER3 induction; co-targeting HER3 with siRNA or HER2 inhibitors enhanced PI3K inhibitor efficacy, establishing a feedback loop limiting PI3K inhibitor effectiveness. |
siRNA knockdown, PI3K inhibitor treatment, Western blotting for pathway activation, co-treatment experiments, xenograft models |
Proceedings of the National Academy of Sciences of the United States of America |
High |
21368164
|
| 2011 |
ErbB3 loss in luminal mammary epithelium of mice impairs Akt and MAPK signaling, reduces luminal cell proliferation and survival, and shifts gene expression toward a basal/stem cell signature. ErbB3 depletion-induced effects were rescued by activation of Akt and MAPK. Interestingly, luminal ErbB3 loss induced IL-6 and other cytokines that increased growth of basal epithelial cells in a paracrine fashion. |
Conditional knockout mice, gene expression profiling, siRNA, Akt/MAPK pathway activation rescue experiments, cytokine analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
22178756
|
| 2013 |
Following heregulin stimulation, erbB3 immunoprecipitates show markedly upregulated kinase activity. Intact activated erbB3 can phosphorylate tyrosine sites in an exogenous peptide substrate, and this activity is abolished by mutagenesis of lysine 723 in the catalytic domain. Enhanced erbB3 kinase activity is dependent on heterointeractions with catalytically active erbB2 (blocked by lapatinib or pertuzumab). Single-particle tracking showed erbB3 homo- and heterodimerization events in real time on live cells. |
Kinase activity assay from immunoprecipitates, K723 mutagenesis, lapatinib/pertuzumab inhibition, single-particle quantum dot tracking on live cells |
Molecular and cellular biology |
High |
24379439
|
| 2013 |
ERBB3 somatic mutations (~11% in colon and gastric cancers) transform colonic and breast epithelial cells in a ligand-independent manner, but oncogenic ERBB3 mutant activity is dependent on kinase-active ERBB2. Anti-ERBB antibodies and small molecule inhibitors block mutant ERBB3-mediated oncogenic signaling in vivo. |
Sequencing of primary tumors, cellular transformation assay, ERBB2 knockdown/inhibition epistasis, in vivo xenograft models |
Cancer cell |
High |
23680147
|
| 2014 |
NEDD4 (E3 ubiquitin ligase) negatively regulates HER3 levels and signaling: NEDD4 WW domains interact with the C-terminal tail of HER3 in a neuregulin-1-independent manner. NEDD4 shRNA knockdown elevated HER3 levels and increased HER3 signaling and cancer cell proliferation in vitro and in vivo. |
Co-immunoprecipitation, domain mapping, shRNA knockdown, proliferation assays, xenograft models, prostate cancer tissue analysis |
Oncogene |
High |
24662824
|
| 2014 |
TX1-85-1, a covalent ligand, forms a bond with Cys721 in the ATP-binding site of HER3 and inhibits HER3 signaling. Derivatization with hydrophobic adamantane (TX2-121-1) enhances inhibition, causes partial HER3 degradation, and interferes with productive heterodimerization of HER3 with HER2 or c-Met, demonstrating that covalent modification of HER3's pseudokinase ATP site is pharmacologically tractable. |
Covalent ligand synthesis, mass spectrometry confirmation of covalent modification, cell signaling Western blots, co-immunoprecipitation of HER3 heterodimers |
Nature chemical biology |
High |
25326665
|
| 2017 |
EGF and NRG induce HER3 phosphorylation via distinct oligomeric mechanisms depending on co-receptor context. NRG-induced HER3 phosphorylation by EGFR requires asymmetric kinase dimerization without higher-order oligomers; EGF-induced HER3 phosphorylation occurs via a noncanonical mechanism within large receptor clusters; NRG-induced HER3 phosphorylation by HER2 requires cluster formation and asymmetric kinase dimerization. |
STORM super-resolution microscopy with pair-correlation analysis, receptor phosphorylation assays, ligand-specific stimulation conditions |
Proceedings of the National Academy of Sciences of the United States of America |
High |
28320942
|
| 2017 |
ROR1 phosphorylates HER3 at Tyr1307 (a previously unidentified site) following neuregulin stimulation, independently of other ErbB family members. Phospho-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex, which methylates MST1 (Hippo kinase) at Lys59, leading to MST1 inactivation and YAP target gene activation, osteoclast differentiation, and bone metastasis. |
Co-immunoprecipitation, phosphospecific antibodies, mutagenesis, RNA-protein complex isolation, methylation assay, in vivo bone metastasis models |
Nature cell biology |
High |
28114269
|
| 2018 |
Lapatinib (ATP-competitive HER2 inhibitor) stabilizes a specific HER2 conformer that drives HER2-HER3 kinase domain heterocomplex formation in a head-to-head orientation distinct from the canonical asymmetric active dimer. This atypical dimer, combined with HER3 ligand NRG, cooperatively promotes proliferation, providing a mechanistic basis for inhibitor-induced paradoxical pro-proliferative signaling. |
FRET-based conformational assay, Co-IP of kinase domain complexes, structural modeling, proliferation assays with lapatinib + NRG combinations |
eLife |
High |
29712619
|
| 2018 |
In untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation but rather by ligand-independent MET activation caused by MET overexpression. MET phosphorylates HER3 via a mechanism not requiring the allosteric site used by canonical co-receptors EGFR/HER2. HER3 preferentially interacts with MET during maturation along the secretory pathway (before MET extracellular domain cleavage), resulting in accumulation of phospho-HER3 in the Golgi. |
Co-immunoprecipitation at different maturation states, phosphorylation assays with MET overexpression, allosteric site mutagenesis, subcellular fractionation |
Oncogene |
High |
30390071
|
| 2020 |
Single-molecule analysis of endogenous HER2-HER3 heterodimers revealed large conformational fluctuations in juxtamembrane and kinase domains. Despite these fluctuations, individual HER2-HER3 heterodimers catalyze tyrosine phosphorylation at an unusually high rate while simultaneously interacting with multiple downstream signaling effectors, explaining the exceptional signaling potency of this heterodimer. |
Single-molecule immunoprecipitation, single-molecule FRET, single-molecule kinase activity assay with endogenous receptors |
eLife |
High |
32267234
|
| 2021 |
Cryo-EM structure of the NRG1β-bound near full-length HER2-HER3 dimer revealed that the HER3 dimerization arm is unresolved because apo HER2 does not undergo the ligand-induced conformational change needed to form a HER3 dimerization arm-binding pocket. The oncogenic HER2(S310F) mutant compensates via a stabilizing interaction with the HER3 dimerization arm. Trastuzumab binds both complexes but pertuzumab does not bind HER2(S310F)-HER3, and the HER2(S310F)-HER3 complex undergoes conformational change to accommodate trastuzumab. |
Cryo-electron microscopy of near full-length HER2-HER3 and HER2(S310F)-HER3 complexes, Fab binding studies |
Nature |
High |
34759323
|
| 2021 |
Co-occurring HER3(E928G) kinase domain mutation enhances HER2/HER3 heterodimerization affinity and reduces neratinib binding to HER2. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, promoting growth, invasiveness, and resistance to HER2-targeted therapies reversible by PI3Kα inhibitors. |
Computational structural modeling, co-immunoprecipitation, phosphorylation assays, cell proliferation/invasion assays, PI3Kα inhibitor rescue |
Cancer cell |
High |
34171264
|
| 2021 |
SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 that attenuates lysosomal degradation of the HER2-HER3 dimer in a Rab4-dependent manner. HRG-mediated signaling supports SorLA transcription downstream of MAPK, creating a feed-forward loop. Loss of SorLA compromised heregulin-induced proliferation and sensitized resistant breast cancer cells to neratinib. |
Co-immunoprecipitation, Rab4 dominant-negative experiments, lysosomal degradation assays, MAPK inhibition, in vivo zebrafish xenograft model |
Oncogene |
Medium |
33420373
|
| 2013 |
MTK1 (MAP3K4/MEKK4) associates with activated HER3 following HRG-beta1 stimulation in an HER2-activation-dependent manner (blocked by lapatinib). MTK1 is required for HER2/HER3-HRG-induced cell migration and extracellular acidification in breast cancer cells; disruption of actin polymerization inhibits HRG-induced MTK1/HER3 association. |
Co-immunoprecipitation, lapatinib treatment, cytochalasin D treatment, MTK1 knockdown, migration/acidification assays |
Cellular signalling |
Medium |
24036211
|
| 2016 |
Hepatocyte-specific knockout of ERBB3 (alone or combined with EGFR) diminishes CCl4-induced liver fibrosis in mice, with maximal reduction in the ERBB3 and EGFR-ERBB3 double knockout models. This suggests that EGFR-ERBB3 heterodimeric signaling in hepatocytes plays a more important role in fibrogenesis than EGFR homodimeric signaling. |
Hepatocyte-specific conditional knockout mice (single and double), CCl4-induced fibrosis model, alpha-SMA quantification, immunohistochemistry |
American journal of physiology. Gastrointestinal and liver physiology |
High |
27586651
|
| 1993 |
Alternative splicing of the c-erbB3 gene produces a 1.4-kb transcript encoding a secreted ErbB3 receptor isoform (erbB3-S), in addition to the full-length transmembrane receptor encoded by the 6.2-kb transcript. |
Northern blot, RACE cloning, cDNA sequencing, genomic structure analysis |
Biochemical and biophysical research communications |
Medium |
7685162
|
| 2024 |
ErbB3 is upregulated in pulmonary artery endothelial cells in pulmonary hypertension. Endothelial cell-specific ErbB3 knockout reduces hypoxia-induced endothelial proliferation, pulmonary artery remodeling, and right ventricular hypertrophy in rodent PH models, while ErbB3 overexpression exacerbates PH. Co-immunoprecipitation and proteomic analysis identified YB-1 as a downstream target; ErbB3 induces nuclear translocation of YB-1, promoting HIF-1/2α transcription. A positive ErbB3-periostin-HIF-1/2α loop was identified. |
Endothelial cell-specific conditional knockout, AAV-mediated overexpression, co-immunoprecipitation, proteomics, nuclear translocation assays, rodent PH models |
Circulation |
High |
38214194
|