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Updated: Mar 1, 2026
Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
Published on: September 25, 2017
Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling
Simon J Cook1, Kate Stuart1, Rebecca Gilley1
1Signalling Programme, The Babraham Institute, Cambridge, UK.
Abstract:
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 prosurvival BCL2 proteins (BCL2, BCL-xL and MCL1) and repressing prodeath proteins (BAD, BIM, BMF and PUMA). This prosurvival 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 prodeath 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 subcellular proteomics it is likely that new roles for ERK1/2, and new substrates, remain to be discovered at the mitochondria and other organelles.
Insights
The ERK1/2 pathway regulates cell fate by influencing mitochondrial apoptosis. It promotes survival by activating BCL2 proteins but can also trigger apoptosis during starvation, impacting cancer and stem cell reprogramming.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Biology
Background:
- The ERK1/2 signaling pathway is crucial for transmitting signals from growth factor receptors to the nucleus, affecting gene expression.
- Activated ERK1/2 also localizes to various organelles, including mitochondria, influencing cell physiology.
- Mitochondria play a central role in regulating cell fate decisions, particularly apoptosis.
Purpose of the Study:
- To review the roles of ERK1/2 signaling at the mitochondria in regulating cell fate.
- To discuss the involvement of ERK1/2 in the BCL2-regulated apoptotic pathway.
- To explore the connection between ERK1/2, mitochondrial dynamics, and metabolic reprogramming.
Main Methods:
- Literature review of studies on ERK1/2 signaling in mitochondria.
- Analysis of ERK1/2's role in regulating BCL2 family proteins (prosurvival and prodeath).
- Examination of recent findings linking ERK1/2 to mitochondrial fission machinery (DRP1).
Main Results:
- ERK1/2 signaling generally promotes cell survival by activating prosurvival BCL2 proteins and inhibiting prodeath proteins.
- Oncogenes exploit this prosurvival signaling for cancer cell survival, informing drug development.
- ERK1/2 can induce prodeath protein NOXA expression, influencing autophagy versus apoptosis decisions under nutrient starvation.
- ERK1/2 signaling is linked to DRP1 and mitochondrial fission, potentially affecting metabolic reprogramming in tumors and stem cells.
Conclusions:
- ERK1/2 signaling at the mitochondria is a key regulator of cell fate, impacting apoptosis and survival.
- Understanding these mitochondrial roles of ERK1/2 offers therapeutic opportunities, particularly in oncology.
- Further research, aided by subcellular proteomics, will likely uncover novel mitochondrial substrates and functions of ERK1/2.
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