Diagrammatic representation of HER2/ERBB2 dimerizations and their respective activated signaling cascades from Reactome pathway database. (A) Constitutive signaling by overexpressed HER2/ERBB2, where it homodimerizes and activates RAS/RAF/MAPK signaling and also shown, trastuzumab as inhibitor; (B) signaling by HER2/ERBB2 KD mutants, where HER2/ERBB2 heterodimerizes and activates P13/Akt, PLCgamma and RAS/RAF/MAPK signaling and also indicates drug resistance; (C) signaling by HER2/ERBB2 ECD mutants, which heterodimerizes and activates P13/Akt, PLCgamma and RAS/RAF/MAPK signaling; and (D) signaling by HER2/ERBB2 TND/JMD mutants, where it heterodimerizes and activates PLCgamma and RAS/RAF/MAPK signaling and shown pertuzumab as inhibitor, but also drug resistance is shown. ECD: extracellular domain; JMD: juxtamembrane domain; KD: kinase domain; TMD: transmembrane domain
We thank Hybrinomics Life Science & Diagnostics LLP, for their willingness to allow public access to their web services, particularly Schrödinger software.
Author contributions
JS: Methodology, Investigation, Writing—original draft. PM: Conceptualization, Methodology, Investigation, Supervision, Writing—review & editing. HV: Formal analysis, Writing—review & editing. All authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
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Availability of data and materials
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
Hu S, Sun Y, Meng Y, Wang X, Yang W, Fu W, et al. Molecular architecture of the ErbB2 extracellular domain homodimer.Oncotarget. 2015;6:1695–706. [DOI] [PubMed] [PMC]
Li E, Hristova K. Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies.Biochemistry. 2006;45:6241–51. [DOI] [PubMed] [PMC]
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, Vos AMd, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.Cancer Cell. 2004;5:317–28. [DOI] [PubMed]
Landgraf R. HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks.Breast Cancer Res. 2007;9:202. [DOI] [PubMed] [PMC]
Furrer D, Paquet C, Jacob S, Diorio C. The Human Epidermal Growth Factor Receptor 2 (HER2) as a Prognostic and Predictive Biomarker: Molecular Insights into HER2 Activation and Diagnostic Implications. In: Lemamy GJ, editor. Cancer Prognosis. IntechOpen; 2018.
Rubin I, Yarden Y. The basic biology of HER2.Ann Oncol. 2001;12 Suppl 1:S3–8. [DOI] [PubMed]
Xu W, Yuan X, Beebe K, Xiang Z, Neckers L. Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity.Mol Cell Biol. 2007;27:220–8. [DOI] [PubMed] [PMC]
Borg JP, Marchetto S, Bivic AL, Ollendorff V, Jaulin-Bastard F, Saito H, et al. ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor.Nat Cell Biol. 2000;2:407–14. [DOI] [PubMed]
Citri A, Gan J, Mosesson Y, Vereb G, Szollosi J, Yarden Y. Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation.EMBO Rep. 2004;5:1165–70. [DOI] [PubMed] [PMC]
Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer.Mol Cancer. 2018;17:58. [DOI] [PubMed] [PMC]
Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J. Identification of autophosphorylation sites of HER2/neu.Cell Growth Differ. 1990;1:3–7.
Pickl M, Ries CH. Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab.Oncogene. 2009;28:461–8. [DOI] [PubMed]
Ricci A, Lanfrancone L, Chiari R, Belardo G, Pertica C, Natali PG, et al. Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase.Oncogene. 1995;11:1519–29. [PubMed]
Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A, et al. The reactome pathway knowledgebase 2022.Nucleic Acids Res. 2022;50:D687–92. [DOI] [PubMed] [PMC]
Li T, Jiang H, Tong Y, Lu J. Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery.J Hematol Oncol. 2018;11:59. [DOI] [PubMed] [PMC]
Ricci AD, Rizzo A, Llimpe FLR, Fabio FD, Biase DD, Rihawi K. Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?Cancers (Basel). 2021;13:1664. [DOI] [PubMed] [PMC]
Rizzo A, Cusmai A, Acquafredda S, Rinaldi L, Palmiotti G. Ladiratuzumab vedotin for metastatic triple negative cancer: preliminary results, key challenges, and clinical potential.Expert Opin Investig Drugs. 2022;31:495–8. [DOI] [PubMed]
Quagliariello V, Laurentiis MD, Cocco S, Rea G, Bonelli A, Caronna A, et al. NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells.Int J Mol Sci. 2020;21:7802. [DOI] [PubMed] [PMC]
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The Protein Data Bank.Nucleic Acids Res. 2000;28:235–42. [DOI] [PubMed] [PMC]
Beard H, Cholleti A, Pearlman D, Sherman W, Loving KA. Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes.PLoS One. 2013;8:e82849. [DOI] [PubMed] [PMC]
Salam NK, Adzhigirey M, Sherman W, Pearlman DA. Structure-based approach to the prediction of disulfide bonds in proteins.Protein Eng Des Sel. 2014;27:365–74. [DOI] [PubMed]
Zhu K, Day T, Warshaviak D, Murrett C, Friesner R, Pearlman D. Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction.Proteins. 2014;82:1646–55. [DOI] [PubMed] [PMC]
Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments.J Comput Aided Mol Des. 2013;27:221–34. [DOI] [PubMed]
Chuang GY, Kozakov D, Brenke R, Comeau SR, Vajda S. DARS (Decoys As the Reference State) potentials for protein-protein docking.Biophys J. 2008;95:4217–27. [DOI] [PubMed] [PMC]
Fernández-Recio J, Sternberg MJE. The 4th meeting on the Critical Assessment of Predicted Interaction (CAPRI) held at the Mare Nostrum, Barcelona.Proteins. 2010;78:3065–6. [DOI]
Kozakov D, Brenke R, Comeau SR, Vajda S. PIPER: an FFT-based protein docking program with pairwise potentials.Proteins. 2006;65:392–406. [DOI] [PubMed]
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool.J Mol Biol. 1990;215:403–10. [DOI] [PubMed]
Madeira F, Pearce M, Tivey ARN, Basutkar P, Lee J, Edbali O, et al. Search and sequence analysis tools services from EMBL-EBI in 2022.Nucleic Acids Res. 2022;50:W276–9. [DOI] [PubMed] [PMC]
McGuffin LJ, Bryson K, Jones DT. The PSIPRED protein structure prediction server.Bioinformatics. 2000;16:404–5. [DOI] [PubMed]
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera--a visualization system for exploratory research and analysis.J Comput Chem. 2004;25:1605–12. [DOI] [PubMed]
Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.Genes Dev. 2007;21:2172–81. [DOI] [PubMed] [PMC]
Bublik DR, Scolz M, Triolo G, Monte M, Schneider C. Human GTSE-1 regulates p21CIP1/WAF1 stability conferring resistance to paclitaxel treatment.J Biol Chem. 2010;285:5274–81. [DOI] [PubMed] [PMC]
Jascur T, Brickner H, Salles-Passador I, Barbier V, Khissiin AE, Smith B, et al. Regulation of p21WAF1/CIP1 stability by WISp39, a Hsp90 binding TPR protein.Mol Cell. 2005;17:237–49. [DOI] [PubMed]
Yu D, Jing T, Liu B, Yao J, Tan M, McDonnell TJ, et al. Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase.Mol Cell. 1998;2:581–91. [DOI] [PubMed]
Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1.Cell. 1998;94:471–80. [DOI] [PubMed]
Roe SM, Ali MMU, Meyer P, Vaughan CK, Panaretou B, Piper PW, et al. The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50cdc37.Cell. 2004;116:87–98. [DOI] [PubMed]
Liu X, Wei B, Shi H, Shan Y, Wang C. Tom70 mediates activation of interferon regulatory factor 3 on mitochondria.Cell Res. 2010;20:994–1011. [DOI] [PubMed]
Yang K, Shi H, Qi R, Sun S, Tang Y, Zhang B, et al. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells.Mol Biol Cell. 2006;17:1461–71. [DOI] [PubMed] [PMC]
Bigenzahn JW, Fauster A, Rebsamen M, Kandasamy RK, Scorzoni S, Vladimer GI, et al. An Inducible Retroviral Expression System for Tandem Affinity Purification Mass-Spectrometry-Based Proteomics Identifies Mixed Lineage Kinase Domain-like Protein (MLKL) as an Heat Shock Protein 90 (HSP90) Client.Mol Cell Proteomics. 2016;15:1139–50. [DOI] [PubMed] [PMC]
Jacobsen AV, Lowes KN, Tanzer MC, Lucet IS, Hildebrand JM, Petrie EJ, et al. HSP90 activity is required for MLKL oligomerisation and membrane translocation and the induction of necroptotic cell death.Cell Death Dis. 2016;7:e2051. [DOI] [PubMed] [PMC]
Zhao XM, Chen Z, Zhao JB, Zhang PP, Pu YF, Jiang SH, et al. Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.Cell Death Dis. 2016;7:e2089. [DOI] [PubMed] [PMC]
Li D, Xu T, Cao Y, Wang H, Li L, Chen S, et al. A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis.Proc Natl Acad Sci U S A. 2015;112:5017–22. [DOI] [PubMed] [PMC]
