Life Sciences Research for Lifelong Health

Pamela Lochhead

All 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.

Selected References
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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


Latest Publications

Control of cell death and mitochondrial fission by ERK1/2 MAP Kinase signalling.

Cook SJ, Stuart K, Gilley R

The FEBS journal
1742-4658: (2017)

PMID: 28548464

Visualisation of Endogenous ERK1/2 in Cells with a Bioorthogonal Covalent Probe.

Sipthorp J, Lebraud H, Gilley R

Bioconjugate chemistry
1520-4812: (2017)

PMID: 28449575

RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.

Galloway A, Saveliev A, Łukasiak S

Science (New York, N.Y.)
352 1095-9203:453-9 (2016)

PMID: 27102483

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

Cell cycle (Georgetown, Tex.)
15 1551-4005:506-18 (2016)

PMID: 26959608

Maternal DNA Methylation Regulates Early Trophoblast Development.

Branco MR, King M, Perez-Garcia V

Developmental cell
36 1878-1551:152-63 (2016)

PMID: 26812015

MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road.

Caunt CJ, Sale MJ, Smith PD

Nature reviews. Cancer
15 1474-1768:577-92 (2015)

PMID: 26399658

Identification of DYRK1B as a substrate of ERK1/2 and characterisation of the kinase activity of DYRK1B mutants from cancer and metabolic syndrome.

Ashford AL, Dunkley TP, Cockerill M

Cellular and molecular life sciences : CMLS
1420-9071: (2015)

PMID: 26346493