Yarden and Sliwkowski 2001: untangling the ErbB signalling network
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.
Overview
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.
- 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.
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.
- A review; structural details of the receptor dimers were resolved later.
- Written before most HER2 and EGFR drugs reached the clinic.
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