My research focuses on kinase biology and how kinase signalling pathways are hijacked in cancer. We combine computational biology with proteomics and cell biology to uncover novel ways to target these dysregulated networks.
The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition. Nature Communications (2020) 11(1):1396–14. PMID: 32170202
PKCε Controls Mitotic Progression by Regulating Centrosome Migration and Mitotic Spindle Assembly. Molecular Cancer Research (2018) 16(1):3-15. PMID: 29021232
PKCɛ switches Aurora B specificity to exit the abscission checkpoint. Nature Communications (2016) ;7:13853. PMID: 28004745
Mitotic catenation is monitored and resolved by a PKCε-regulated pathway. Nature Communications (2014); 5(1):5685. PMID: 25483024
Kinases are attractive therapeutic targets for cancer. Approximately 25% of the known 535 kinases are associated with cancer through mutation, overexpression or aberrant signalling. However, the majority of therapies targeting kinases in cancer patients fail, due to development of resistance, or toxicity. We are working to develop new approaches to target cancer kinases to overcome these limitations.
We have described a novel mechanism by which kinase substrate specificity is regulated. Modification of the kinase activation loop by phosphorylation or mutation can alter substrate specificity. In cancer, this can lead to the rewiring of signalling pathways to promote oncogenic properties. How substrate specificity is determined, particularly relating to activation-loop modification is a hitherto unexplored niche which will provide new insights in the targeting of kinases in cancer.
This now provides an exciting opportunity to significantly advance understanding of the fundamental biology of kinase regulation. These new insights will enable the discovery of previously unknown or undefined signalling nodes and establish a route to developing new kinase inhibitors for personalised cancer therapy through the delivery of a high-resolution understanding of kinase regulation and dysregulation in cancer.
A cancer-associated, genome protective programme engaging PKCε Parker PJ, Lockwood N, Davis K et al. Advances in Biological Regulation (2020) 78(7)
Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition (Nature Communications, (2020), 11, 1, (1396), 10.1038/s41467-020-15163-6) Kelly JR, Martini S, Brownlow N et al. Nature Communications (2020) 11(1)
The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition Kelly JR, Martini S, Brownlow N et al. Nature Communications (2020) 11(7)
Equivocal, explicit and emergent actions of PKC isoforms in cancer Parker PJ, Brown SJ, Calleja V et al. Nature Reviews Cancer (1)
Specific mechanisms of chromosomal instability indicate therapeutic sensitivities in high-grade serous ovarian carcinoma. Mcclelland S, Tamura N, Shaikh N et al. Cancer Research (2020) (1)
A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest Deiss K, Lockwood N, Howell M et al. Nucleic Acids Research (2019) 47(7) 2906-2921
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface Claus J, Patel G, Autore F et al. eLife (2018) 7(7)
PKCϵ controls mitotic progression by regulating centrosome migration and mitotic spindle assembly Martini S, Soliman T, Gobbi G et al. Molecular Cancer Research (2018) 16(7) 3-15
PKCϵ switches Aurora B specificity to exit the abscission checkpoint Pike T, Brownlow N, Kjaer S et al. Nature Communications (2016) 7(7)
Regulation of the cytokinesis cleavage furrow by PKCε Brownlow N, Pike T, Crossland V et al. Biochemical Society Transactions (2014) 42(7) 1534-1537For additional publications, please click here