{"entity":{"id":"paper-yarden-sliwkowski-erbb-network-nrmcb-2001","kind":"paper","name":"Yarden and Sliwkowski 2001: untangling the ErbB signalling network","aka":[],"tldr":"The classic account of the HER family of receptors, explaining why HER2 is such a powerful cancer driver: it is the preferred partner for the other three receptors and turns their signals up, which is what trastuzumab and later HER2 drugs exploit.","summary":"Yarden and Sliwkowski described the four ErbB receptors (EGFR, HER2, HER3 and HER4) as a layered signalling network in which ligands select receptor pairs, the pairs determine which intracellular pathways are engaged, and the network's outputs control proliferation, survival and differentiation. They emphasised that HER2 has no ligand of its own but is the preferred dimerisation partner, that HER3 lacks kinase activity but couples strongly to PI3K, and that HER2 overexpression or EGFR mutation deregulates the whole network, which explains the activity of antibodies and kinase inhibitors against these receptors.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/35052073"}],"tags":[],"related":["paper-lemmon-schlessinger-rtk-signalling-cell-2010","paper-slamon-her2-amplification-science-1987"],"cancers":[],"sections":[],"technologies":[],"targets":["egfr","her2","her3","erbb4"],"drugs":[],"companies":["roche-genentech"],"institutions":[],"pathways":["rtk-activation"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature Reviews Molecular Cell Biology","year":2001,"doi":"10.1038/35052073","authors":"Yarden Y, Sliwkowski MX.","paperType":"review","findings":["The four ErbB receptors form a network of homo- and heterodimers whose composition determines signalling output.","HER2 is ligand-less but the preferred and most potent dimerisation partner; HER3 is kinase-impaired but a strong activator of PI3K.","Deregulation by HER2 amplification or EGFR mutation underlies many cancers and is targetable with antibodies and small molecules."],"whatItMeans":"This review is the conceptual basis for trastuzumab, pertuzumab, HER2 antibody-drug conjugates and EGFR inhibitors, and for the HER3-mediated resistance that later drugs try to overcome.","caveats":["A review; structural details of the receptor dimers were resolved later.","Written before most HER2 and EGFR drugs reached the clinic."],"changedPractice":false},"route":"/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/","neighbours":{"paper":[{"id":"paper-lemmon-schlessinger-rtk-signalling-cell-2010","kind":"paper","name":"Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases","route":"/key-papers/paper-lemmon-schlessinger-rtk-signalling-cell-2010/"},{"id":"paper-slamon-her2-amplification-science-1987","kind":"paper","name":"Slamon 1987: HER2 gene amplification marks an aggressive form of breast cancer","route":"/key-papers/paper-slamon-her2-amplification-science-1987/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"her3","kind":"target","name":"HER3","route":"/targets/her3/"},{"id":"erbb4","kind":"target","name":"HER4 (ERBB4)","route":"/targets/erbb4/"}],"company":[{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"}],"pathway":[{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"idea":[{"id":"idea-alpha-after-adc","kind":"idea","name":"Alpha radioligands after ADC failure","route":"/ideas/idea-alpha-after-adc/"},{"id":"idea-biomarker-quadruplet-gastric","kind":"idea","name":"Biomarker-directed first-line quadruplets in gastric cancer","route":"/ideas/idea-biomarker-quadruplet-gastric/"},{"id":"idea-bio2-intraventricular-car-t","kind":"idea","name":"Deliver CAR-T cells straight into the fluid around the brain","route":"/ideas/idea-bio2-intraventricular-car-t/"},{"id":"idea-dual-payload-first","kind":"idea","name":"Dual-payload ADCs in first line to prevent resistance","route":"/ideas/idea-dual-payload-first/"},{"id":"idea-her2-adc-serous-endometrial","kind":"idea","name":"HER2 ADCs as standard for HER2-positive serous endometrial cancer","route":"/ideas/idea-her2-adc-serous-endometrial/"},{"id":"idea-bio1-antigen-mapping-at-progression","kind":"idea","name":"Re-map the tumour's surface proteins before choosing the next antibody drug","route":"/ideas/idea-bio1-antigen-mapping-at-progression/"},{"id":"idea-bio2-transferrin-shuttle-adc","kind":"idea","name":"Use the brain's own transport door to carry antibody drugs across","route":"/ideas/idea-bio2-transferrin-shuttle-adc/"}]}}