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Control of cell death and mitochondrial fission by ERK 1/2 MAP kinase signalling
Author(s) -
Cook Simon J.,
Stuart Kate,
Gilley Rebecca,
Sale Matthew J.
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14122
Subject(s) - microbiology and biotechnology , biology , mitochondrial fission , mitochondrion , mapk/erk pathway , programmed cell death , cell fate determination , golgi apparatus , nrf1 , autophagy , endoplasmic reticulum , signal transduction , kinase , endosome , apoptosis , transcription factor , intracellular , mitochondrial biogenesis , biochemistry , gene
The ERK 1/2 signalling pathway is best known for its role in connecting activated growth factor receptors to changes in gene expression due to activated ERK 1/2 entering the nucleus and phosphorylating transcription factors. However, active ERK 1/2 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 ERK 1/2 signalling at the mitochondria that are involved in regulating cell fate decisions. First, we describe the prominent role of ERK 1/2 in controlling the BCL 2‐regulated, cell‐intrinsic apoptotic pathway. In most cases ERK 1/2 signalling promotes cell survival by activating prosurvival BCL 2 proteins ( BCL 2, BCL ‐ x L and MCL 1) 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, ERK 1/2 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 ERK 1/2 signalling, DRP 1 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 ERK 1/2, and new substrates, remain to be discovered at the mitochondria and other organelles.