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Title: The pseudokinase HER3 : structure/function relationships and inhibitor-induced signalling
Author: Claus, J.
ISNI:       0000 0004 5351 6895
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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The receptor tyrosine kinase HER3, a pseudokinase in the epidermal growth factor receptor (EGFR) family, is involved in responses to ligands and in the acquired resistance against HER2-directed targeted therapy in breast cancer. In this thesis I aim to further investigate the structure/function relationships at the basis of HER2- HER3 heterodimerisation, particularly in response to inhibitor treatment. The data presented here shows that in HER2+ breast cancer cells treated with the HER2 inhibitor lapatinib, stimulation with the HER3 ligand NRG is able to not only rescue cytotoxicity, but even promote proliferation in a drug-growth factor cooperative manner. We show that in response to lapatinib treatment, inactive heterodimers of HER2-HER3 can form, and that these heterodimers adopt a different conformation to the canonical, asymmetric active heterodimer. Instead, lapatinib promotes a head-to-head, symmetrical heterodimer, in which the α-C helices of both receptors form the interface. For the formation of the inactive heterodimer, as well as for promoting ligandinduced signalling, we show that HER3 requires ATP-binding capability. Although there are implications that HER3 retains a measure of catalytic activity, I show that the ATP-binding requirement for dimerisation and signalling is independent of activity. To highlight this, I have identified a Src/Abl kinase inhibitor, bosutinib, which has high affinity to HER3. SKBR3 cells treated with bosutinib in the absence of exogenously added ligand show an increase in proliferation in 2D and 3D culture models. This indicates an importance for conformational stabilisation of the HER3 kinase domain in the formation of active signalling heterodimers. As a pseudokinase, the role of HER3 may be conceived as being of lesser importance than that of its heterodimerisation partners such as HER2. The structure/function studies presented here show that HER3 remains of great importance in providing an allosteric platform for HER2, together forming the HER2-HER3 oncogenic heterodimer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available