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

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.

Silencing of keratin 17 by lentivirus‑mediated short hairpin RNA inhibits the proliferation of PANC‑1 human pancreatic cancer cells

“…The present study demonstrated that KRT17 knockdown decreased the level of ERK1/2 phosphorylation, suggesting that upregulation of KRT17 participated in EMT and migration in PAC tumorigenesis. In the majority of cancer types, ERK1/2 signaling promotes cell survival by inhibiting the function of pro-death proteins, including Bad (47). In the present study, Bad phosphorylation increased following KRT17 silencing using KRT17-shRNA lentivirus transfection.…”

Butyrate Inhibits Deoxycholic‐Acid‐Resistant Colonic Cell Proliferation via Cell Cycle Arrest and Apoptosis: A Potential Pathway Linking Dietary Fiber to Cancer Prevention

“…[ 41,42 ] Similar to the dual functional role of p38 activation, the ERK1/2 activation cannot only promote cell proliferation but also drive cell senescence/apoptosis depending on dose, duration, cell type, and other factors. [ 43,44 ] However, it remains an ongoing research how the cells “decide” to respond to stimuli (e.g., butyrate treatment) by preferentially undergoing cell proliferation or cell cycle arrest/apoptosis. Our butyrate‐treatment data (Figure 6) suggest that an increase in activation of p38 and ERK1/2 may inhibit cell proliferation in HCT‐116 cells while a decrease in p38 activation may also decrease cell proliferation in DCA‐RCL cells.…”

Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c‐MYC axis in breast cancer

“…13 The extracellular signal-regulated kinase 1/2 (ERK1/2) can be activated and/ or up-regulated by upstream kinases, transcription factors and/ or differentiation factor. [14][15][16] Activated ERK1/2 translocates to the cell nucleus and then phosphorylates a series of transcription factors, such as c-MYC, FOS, FRA1 and EGR1. [17][18][19][20][21][22][23] These ERK1/2-activated downstream factors further regulate many cellular functions, including proliferation, differentiation and transformation.…”