ArticleProceedings of the National Academy of Sciences of the United States of America2010
ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 269 papers.
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269 citing papers in PubMed, 467 citations in OpenAlex.
- Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.Oncotarget · 2016Trial
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- Modulating pseudokinase conformation from the ATP-binding site.Structure (London, England : 1993) · 2026Article
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- The multifaceted roles of receptor tyrosine pseudokinases in cellular signalling.Biochemical Society transactions · 2026Review
- Human epidermal growth factor receptor 3-targeted near-infrared photoimmunotherapy in a xenograft mouse model of breast cancer.BMC cancer · 2026Article
- Roles of Her3 in carcinogenesis and advances in Her3-targeted cancer therapy.Discover oncology · 2026Review
- The role of kinase domain dimerization in EGFR activation.Structure (London, England : 1993) · 2026Article
- The Impact of HER3 Dynamics Altered by HER3-DXd Alone and in Combination with Driver Oncogene Inhibitors on HER3-DXd Efficacy.International journal of molecular sciences · 2026Article
- Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A combined strategy of EGFR-MET bispecific antibody and HER3 ADC to overcome osimertinib resistance in NSCLC.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- HER3-targeting Antibody-drug Conjugates Therapy for Solid Tumors: Recent Advances and Future Potentials.Current medicinal chemistry · 2026Review
- Multiple Roles for Neuregulins and Their v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog Receptors in Neurodegenerative Disease Pathogenesis and Therapy.The American journal of pathology · 2025Review
- Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families.Biochemical Society transactions · 2025Review
- NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.Science advances · 2025Article
- HER3: Unmasking a twist in the tale of a previously unsuccessful therapeutic pursuit targeting a key cancer survival pathway.Genes & diseases · 2025Review
- Emerging importance of HER3 in tumorigenesis and cancer therapy.Nature reviews. Clinical oncology · 2025Review
- A Structural Insight Into Two Important ErbB Receptors (EGFR and HER2) and Their Relevance to Non-Small Cell Lung Cancer.Archiv der Pharmazie · 2025Review
- Water-Soluble Curcumin Derivatives Including Aza-Crown Ether Macrocycles as Enhancers of Their Cytotoxic Activity.Chemistry & biodiversity · 2025Article
- PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.EMBO molecular medicine · 2025Article
209 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residues-including the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region--although it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a K(d) of approximately 1.1 microM. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened alphaC-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the "inactive-like" configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.