Life Sciences Research for Lifelong Health

Simon Cook

Research Summary

One of the keys to understanding lifelong health is to understand the signalling pathways that operate inside cells and govern key fate decisions such as cell death, cell survival, cell division or cell senescence (collectively cell longevity).  These signalling pathways involve enzymes called ‘protein kinases’ that attach phosphate groups to specific cellular proteins, thereby controlling their activity, location or abundance. In this way protein kinases orchestrate the cellular response to growth factors, nutrient availability or stress and damage.

Ageing results in part from the imbalance between cellular damage, accrued throughout life, and the progressive decline in stress response and repair pathways. We are interested in how protein kinases function in stress responses, the removal of damaged cellular components (e.g. autophagy, see also Nicholas Ktistakis and Oliver Florey) and the control of cellular lifespan. We believe this will enhance our understanding of how the normal declines in these processes drive ageing.

Signalling pathways are frequently de-regulated in certain age-related diseases – notably in cancer, inflammation and neurodegeneration – and many protein kinases are attractive drug targets. Consequently we translate our basic knowledge of signalling through collaborations with charities and pharmaceutical companies (e.g. AstraZeneca and MISSION Therapeutics).

Latest Publications

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

Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

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PloS one, 12, 1932-6203, e0184907, 2017

PMID: 28931068

Control of cell death and mitochondrial fission by ERK1/2 MAP Kinase signalling.
Cook SJ, Stuart K, Gilley R, Sale MJ

The ERK1/2 signalling pathway is best known for its role in connecting activated growth factor receptors to changes in gene expression due to activated ERK1/2 entering the nucleus and phosphorylating transcription factors. However, active ERK1/2 also translocate to a variety of other organelles including the endoplasmic reticulum, endosomes, golgi and mitochondria to access specific substrates and influence cell physiology. In this article we review two aspects of ERK1/2 signalling at the mitochondria that are involved in regulating cell fate decisions. First, we describe the prominent role of ERK1/2 in controlling the BCL2-regulated, cell-intrinsic apoptotic pathway. In most cases ERK1/2 signalling promotes cell survival by activating pro-survival BCL2 proteins (BCL2, BCL-xL and MCL1) and repressing pro-death proteins (BAD, BIM, BMF and PUMA). This pro-survival signalling is co-opted by oncogenes to confer cancer cell-specific survival advantages and we describe how this information has been used to develop new drug combinations. However, ERK1/2 can also drive the expression of the pro-death protein NOXA to control 'autophagy or apoptosis' decisions during nutrient starvation. We also describe recent studies demonstrating a link between ERK1/2 signalling, DRP1 and the mitochondrial fission machinery and how this may influence metabolic reprogramming during tumorigenesis and stem cell reprogramming. With advances in sub-cellular proteomics it is likely that new roles for ERK1/2, and new substrates, remain to be discovered at the mitochondria and other organelles. This article is protected by copyright. All rights reserved.

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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, Kidger A, Okkenhaug H, Saba-El-Leil MK, Meloche S, Caunt CJ, Cook S, Heightman TD

The RAS-RAF-MEK-ERK pathway has been intensively studied in oncology with RAS known to be mutated in ~30% of all human cancers. The recent emergence of ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding of ERK1/2 behaviour following small molecule inhibition. Although fluorescent fusion proteins and fluorescent antibodies are well-established methods to visualise proteins, we show that ERK1/2 can be visualised via a less invasive approach based on a two-step process using Inverse Electron Demand Diels-Alder cycloaddition. Our previously reported TCO-tagged covalent ERK1/2 inhibitor was used in a series of imaging experiments following a click reaction with a tetrazine-tagged fluorescent dye. Although limitations were encountered with this approach, endogenous ERK1/2 was successfully imaged in cells and 'on target' staining was confirmed by overexpressing DUSP5, a nuclear ERK1/2 phosphatase which anchors ERK1/2 in the nucleus.

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Bioconjugate chemistry, , 1520-4812, , 2017

PMID: 28449575

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cell biology
protein kinases
stress responses

Group Members

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