Pamela LochheadAll living cells constantly sense and respond to their environment. Inside the cell, there is a complex network of signalling pathways, which regulate all cellular decisions from conception to old age. Abnormal signalling pathways cause disease; including developmental defects, inflammation, diabetes, cancer and neurodegeneration. Furthermore, signalling pathways can be manipulated with medicines to treat disease. Therefore, it is critical to understand the molecular mechanisms by which signalling pathways function in healthy and diseased cells.
My research focuses on the evolutionary conserved MAP kinase signalling pathways concentrating on the least well studied ERK5 pathway. MAP Kinase pathways are 3-tiered hierarchical protein kinase cascades that regulate key cell fate decisions. The best-understood example is the RAS-regulated RAF-MEK1/2-ERK1/2 cascade, which connects growth factors receptors to changes in gene expression through ERK-catalysed phosphorylation of ETS and AP-1 transcription factors. Components of the ERK5 pathway are ubiquitously expressed and play a key role in determining embryonic stem cell identity as well as the development of the musculoskeletal and cardiovascular systems. ERK5 is an unusual kinase as it possesses a unique large C-terminal extension containing a nuclear localisation signal and a transcriptional trans-activation domain. I am studying the molecular mechanisms by which ERK5 signals and regulates gene expression.
- Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation. Lochhead PA, Clark J, Wang LZ, Gilmour L, Squires M, Gilley R, Foxton C, Newell DR, Wedge SR, Cook SJ. Cell Cycle. 2016;15(4):506-18. doi: 10.1080/15384101.2015.1120915. PMID: 26959608
- A novel DYRK1B inhibitor AZ191 demonstrates that DYRK1B acts independently of GSK3β to phosphorylate cyclin D1 at Thr(286), not Thr(288). Ashford AL, Oxley D, Kettle J, Hudson K, Guichard S, Cook SJ, Lochhead PA. Biochem J. 2014 Jan 1;457(1):43-56. doi: 10.1042/BJ20130461. PMID: 24134204
- ERK5 and its role in tumour development. Lochhead PA, Gilley R, Cook SJ. Biochem Soc Trans. 2012 Feb;40(1):251-6. doi: 10.1042/BST20110663. Review. PMID: 22260700
- Protein kinase activation loop autophosphorylation in cis: overcoming a Catch-22 situation. Lochhead PA. Sci Signal. 2009 Jan 20;2(54):pe4. doi: 10.1126/scisignal.254pe4. PMID: 19155529
- A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation. Lochhead PA, Kinstrie R, Sibbet G, Rawjee T, Morrice N, Cleghon V. Mol Cell. 2006 Nov 17;24(4):627-33. PMID: 17188038
- Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Lochhead PA, Sibbet G, Morrice N, Cleghon V. Cell. 2005 Jun 17;121(6):925-36. PMID: 15960979
Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2.
Kidger AM, Munck JM, Saini HK
Molecular cancer therapeutics
Odle RI, Walker SA, Oxley D
Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
Sale MJ, Minihane E, Monks NR
10 2041-1723:5167 (2019)
Myers SM, Miller DC, Molyneux L
European journal of medicinal chemistry
178 1768-3254:530-543 (2019)
MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF amplification whereas KRAS amplification promotes EMT-chemoresistance.
Sale MJ, Balmanno K, Saxena J
10 2041-1723:2030 (2019)
Over-expressed, N-terminally truncated BRAF is detected in the nucleus of cells with nuclear phosphorylated MEK and ERK.
Hey F, Andreadi C, Noble C
4 2405-8440:e01065 (2018)
Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors.
Prescott JA, Cook SJ
7 2073-4409: (2018)
Kidger AM, Sipthorp J, Cook SJ
Pharmacology & therapeutics
Kidger AM, Cook SJ
The FEBS journal
285 1742-4658:42-45 (2018)
Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: A role for spleen tyrosine kinase and exosome release.
Dautova Y, Kapustin AN, Pappert K
Journal of molecular and cellular cardiology
ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.
Darling NJ, Balmanno K, Cook SJ
12 1932-6203:e0184907 (2017)
Cook SJ, Stuart K, Gilley R
The FEBS journal