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ERK signalling: a master regulator of cell behaviour, life and fate

Nature Reviews Molecular Cell Biology volume 21, pages 607–632 (2020)Cite this article

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Abstract

The proteins extracellular signal-regulated kinase 1 (ERK1) and ERK2 are the downstream components of a phosphorelay pathway that conveys growth and mitogenic signals largely channelled by the small RAS GTPases. By phosphorylating widely diverse substrates, ERK proteins govern a variety of evolutionarily conserved cellular processes in metazoans, the dysregulation of which contributes to the cause of distinct human diseases. The mechanisms underlying the regulation of ERK1 and ERK2, their mode of action and their impact on the development and homeostasis of various organisms have been the focus of much attention for nearly three decades. In this Review, we discuss the current understanding of this important class of kinases. We begin with a brief overview of the structure, regulation, substrate recognition and subcellular localization of ERK1 and ERK2. We then systematically discuss how ERK signalling regulates six fundamental cellular processes in response to extracellular cues. These processes are cell proliferation, cell survival, cell growth, cell metabolism, cell migration and cell differentiation.

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Fig. 1: ERK activation and subcellular localization.
Fig. 2: ERK regulation of cell proliferation.
Fig. 3: ERK regulation of cell survival.
Fig. 4: ERK regulation of cell growth.
Fig. 5: ERK regulation of cell metabolism.
Fig. 6: ERK regulation of cell motility through formation of lamellipodia and actomyosin contractility.
Fig. 7: ERK regulation of cell motility through focal adhesion turnover and transcriptional control.
Fig. 8: ERK regulation of embryonic stem cell self-renewal and differentiation.
Fig. 9: ERK regulation of cell differentiation and development.

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Acknowledgements

The authors thank C. Baril and D. Kachaner for critical reading of the manuscript. J.G. was supported by a scholarship from the Fonds de Recherche du Québec – Santé. M.T holds an Impact Grant from the Canadian Cancer Society (706165), a Foundation Grant from the Canadian Institutes for Health Research (FDN388023) and a Canada Research Chair in Intracellular Signalling.

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  1. These authors contributed equally: Hugo Lavoie, Jessica Gagnon

Authors and Affiliations

  1. Laboratory of Intracellular Signalling, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada

    Hugo Lavoie, Jessica Gagnon & Marc Therrien

  2. Department of Pathology and Cellular Biology, Université de Montréal, Montreal, QC, Canada

    Marc Therrien

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  1. Hugo Lavoie
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  2. Jessica Gagnon
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The authors contributed equally to all aspects of the article.

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Correspondence to Marc Therrien.

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Glossary

Regulon

Group of genes that are regulated as a single unit, generally under the control of a common regulatory transcription factor that acts as a repressor or activator of gene expression.

Mediator complex

Multiprotein transcription co-activator conserved in all eukaryotes that transmits signals between transcription factors and the RNA polymerase II machinery through direct physical interactions.

ETS family

Transcription activators and inhibitors that share the E26 transformation-specific DNA-binding domain, which associates with DNA motifs encompassing the consensus sequence GGA(A/T).

TPA response element

DNA motif with the consensus sequence TGA(G/C)TCA that serves as a binding site for the AP-1 transcription factor dimers JUN–JUN and JUN–FOS.

cAMP response element

DNA motif with the consensus sequence TGACGTCA that serves as a binding site for the AP-1 transcription factor dimers JUN–ATF2 and ATF2–ATF2 and for ATF1 and CREB family dimers.

Intrinsic apoptosis pathway

Signalling pathway activated by environmental stresses and sensed by BCL-2 family proteins; leads to apoptosis through mitochondrial membrane permeabilization and release of cytochrome c.

Extrinsic apoptosis pathways

Signalling pathways activated by agonists of cell death receptors such as FAS, tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF, which lead to apoptosis through formation of death-inducing signalling complexes.

12-O-Tetradecanoylphorbol-13-acetate

(TPA). Synthetic phorbol ester analogue with potent oncogenic properties that stimulates protein kinase C and multiple downstream events, including hyperactivation of the RAS–ERK signalling cascade.

Oxidative phosphorylation

(OXPHOS). Metabolic process by which an electron transport chain in the inner membrane of mitochondria generates ATP through oxidation of tricarboxylic acid cycle intermediates (NADH or FADH2).

Glycolytic flux

Series of ten metabolic reactions within the glycolysis pathway that lead to the conversion of glucose into pyruvate and that generate the free energy required to form the high-energy molecules ATP and NADH.

Mechanotransduction

Process by which cells sense and transmit mechanical cues from their immediate environment through a series of signalling relays that trigger biological responses.

Focal adhesions

Adhesive contacts between the cell and the extracellular matrix that sense and transmit mechanical forces between integrins and the actin cytoskeleton on engagement of the cell with the extracellular matrix.

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Lavoie, H., Gagnon, J. & Therrien, M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol 21, 607–632 (2020). https://doi.org/10.1038/s41580-020-0255-7

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